Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases

ABSTRACT

Novel compounds of Formula ##STR1## are disclosed. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering a compound of the above formula to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of application Ser. No.08/418,323 filed on Apr. 7, 1995, abandoned, the disclosure of which isincorporated herein by reference thereto.

BACKGROUND

International Publication Number WO92/11034, published Jul. 9, 1992,discloses a method of increasing the sensitivity of a tumor to anantineoplastic agent, which tumor is resistant to the antineoplasticagent, by the concurrent administration of the antineoplastic agent anda potentiating agent of the formula: ##STR2## wherein Y' is hydrogen,substituted carboxylate or substituted sulfonyl. Examples of suchpotentiating agents include 11-(4-piperidylidene)-5H-benzo5,6!cyclohepta 1,2-b!pyridines such as Loratadine.

To acquire transforming potential, the precursor of the Ras oncoproteinmust undergo farnesylation of the cysteine residue located in acarboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzesthis modification, farnesyl protein transferase, have therefore beensuggested as anticancer agents for tumors in which Ras contributes totransformation. Mutated, oncogenic forms of ras are frequently found inmany human cancers, most notably in more than 50% of colon andpancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837,1993).

A welcome contribution to the art would be compounds useful for theinhibition of farnesyl protein transferase. Such a contribution isprovided by this invention.

SUMMARY OF THE INVENTION

Inhibition of farnesyl protein transferase by tricyclic compounds ofthis invention has not been reported previously. Thus, this inventionprovides a method for inhibiting farnesyl protein transferase usingtricyclic compounds of this invention which: (i) potently inhibitfarnesyl protein transferase, but not geranylgeranyl protein transferaseI, in vitro; (ii) block the phenotypic change induced by a form oftransforming Ras which is a farnesyl acceptor but not by a form oftransforming Ras engineered to be a geranylgeranyl acceptor; (iii) blockintracellular processing of Ras which is a farnesyl acceptor but not ofRas engineered to be a geranylgeranyl acceptor; and (iv) block abnormalcell growth in culture induced by transforming Ras.

This invention provides a method for inhibiting the abnormal growth ofcells, including transformed cells, by administering an effective amountof a compound of this invention. Abnormal growth of cells refers to cellgrowth independent of normal regulatory mechanisms (e.g., loss ofcontact inhibition). This includes the abnormal growth of: (1) tumorcells (tumors) expressing an activated Ras oncogene; (2) tumor cells inwhich the Ras protein is activated as a result of oncogenic mutation inanother gene; and (3) benign and malignant cells of other proliferativediseases in which aberrant Ras activation occurs.

The compounds useful in the claimed methods are novel compoundsrepresented by Formula (1.0) ##STR3## wherein: A and B are independentlyselected from H, halo or C₁ -C₆ alkyl;

Z is N or CH;

W is CH, CH₂, O or S, wherein the dotted line to W represents a doublebond which is present when W is CH;

X is C, CH or N, wherein the dotted line connecting X to the tricyclicring system represents a double bond which is present when X is C;

R¹ is selected from:

1) a group of the formula: ##STR4## or disulfide dimers thereof; 2) agroup of the formula: ##STR5## 3) a group of the formula: ##STR6##wherein W, A and B are as defined above; 4) a group of the formula:##STR7## 5) a group of the formula: ##STR8## wherein R⁸⁰ is selectedfrom H or --C(O)OR⁹⁰ wherein R⁹⁰ is a C₁ -C₆ alkyl group (e.g.,--C(CH₃)₃), and R⁸⁵ is a C₁ -C₆ alkoxy group (e.g., p-OCH₃); and

6) a group of the formula: ##STR9## wherein: (a) T is selected from:##STR10## (b) x is 0, 1, 2, 3, 4, 5 or 6; (c) each R^(a) and each R^(b)is independently selected from H, aryl, alkyl, alkoxy, aralkyl, amino,alkylamino, heterocyloalkyl, --COOR⁶⁰, --NH{C(O)}_(z) R⁶⁰ (wherein z is0 or 1), or --(CH)_(w) S(O)_(m) R⁶⁰ (wherein w is 0, 1, 2 or 3, and m is0, 1 or 2); or R^(a) and R^(b) taken together can represent cycloalkyl,═N--O-alkyl, ═O or heterocycloalkyl; with the proviso that for the samecarbon, R^(a) is not selected from alkoxy, amino, alkylamino or--NH{C(O)}_(z) R⁶⁰ when R^(b) is selected from alkoxy, amino, alkylaminoor --NH{C(O)}_(z) R⁶⁰ ; and with the proviso that when T is a singlebond, for the first carbon containing R^(a) and R^(b), R^(a) and R^(b)are not selected from alkoxy, alkylamino, amino or --NHR⁶⁰ (i.e.,--NH{C(O)}_(z) R⁶⁰ wherein z is 0) (i.e., R^(a) and R^(b) on the firstcarbon bound to T, when T is a single bond, are not alkoxy, alkylamino,amino or --NHR⁶⁰); and

(d) R⁹² can represent H, alkyl, aryl, aryloxy, arylthio, aralkoxy,aralkyl, heteroaryl or heterocycloalkyl;

R⁶⁰ represents H, alkyl, aryl or aralkyl;

R⁴ is H or C₁ -C₆ alkyl;

R² is selected from: H, --C(O)OR⁶, --C(O)NR⁶ R⁷, C₁ -C₈ alkyl, C₂ -C₈alkenyl, C₂ -C₈ alkynyl, substituted (C₁ -C₈)alkyl, substituted (C₂-C₈)alkenyl, substituted (C₂ -C₈)alkynyl, wherein said substitutedgroups have one or more substituents selected from:

1) aryl, arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl,B-substituted aryl, B-substituted arylalkyl, B-substitutedheteroarylalkyl, B-substituted heteroaryl or B-substitutedheterocycloalkyl, wherein B is selected from C₁ -C₄ alkyl, --(CH₂)_(n)OR⁶, --(CH₂)_(n) NR⁶ R⁷ and halo;

2) C₃ -C₆ cycloalkyl;

3) --OR⁶ ;

4) --SH or --S(O)_(t) R⁶ ;

5) --NR⁶ R⁷ ;

6) --N(R⁶)--C(O)R⁷ ;

7) --N(R⁶)--C(O)NR⁷ R¹² ;

8) --O--C(O)NR⁶ R⁷ ;

9) --O--C(O)OR⁶ ;

10) --SO₂ NR⁶ R⁷ ;

11) --N(R⁶)--SO₂ --R⁷ ;

12) --C(O)NR⁶ R⁷ ;

13) --C(O)OR⁶ ; and

provided where R¹ is D, R² is not H or C₁ -C₈ alkyl, and where R¹ is Dand R² is substituted C₁ -C₈ alkyl, the substituents on said alkyl groupare not substituents 3), 4), 5), 9), or 13); D is --C(O)--CH₂ --R⁵,--C(O)--O--R⁵ or --C(O)--NH--R⁵, wherein R⁵ is pyridyl, pyridyl N-oxide,##STR11## or a piperidinyl group of the formula ##STR12## wherein R¹¹represents H, C₁ -C₆ alkyl, haloalkyl or --C(O)--R⁹ wherein R⁹ is C₉ -C₆alkyl, C₁ -C₆ alkoxy or --NH(R¹⁰) wherein R¹⁰ is H or alkyl, or thegroup --C(O)--R⁹ represents an acyl radical of a naturally occurringamino acid;

R⁶, R⁷ and R¹² are independently selected from H, C₁ -C₄ alkyl, (C₃-C₆)cycloalkyl, aryl, arylalkyl (i.e., aralkyl), heteroaryl,heteroarylalkyl, heterocycloalkyl, substituted (C₁ -C₄)alkyl,substituted (C₃ -C₆)cycloalkyl, substituted aryl, substituted arylalkyl,substituted heteroaryl, substituted heteroarylalkyl or substitutedheterocycloalkyl, wherein said substituted groups have one or moresubstituents (e.g., 1-3) selected from: C₁ -C₄ alkoxy, aralkyl,heteroarylalkyl, --NO₂, C₃ -C₁₀ -alkoxyalkoxy (e.g., --O--(C₁-C₄)alkyl-O--(C₁ -C₄)alkyl), (C₃ -C₆) cycloalkyl (e.g., cyclopropyl orcyclohexyl), aryl, --CN, nitrophenyl, methylenedioxy-phenyl, heteroaryl,heterocycloalkyl, halo, --OH, --C(O)R¹⁴, --C(O)NR⁶ R⁷, --N(R⁶)C(O)R¹⁴,--S(O)_(t) R¹⁴ (e.g., --S--(C₁ -C₄)alkyl and --SO₂ R¹⁴) or --NR⁹⁵ R¹⁵ ;provided that R⁶, R⁷ and R¹² are not --CH₂ OH or --CH₂ NR⁹⁵ R¹⁵ whensaid R⁶, R⁷ or R¹² is directly bonded to a heteroatom, and furtherprovided that R⁶ is not H for groups 4) and 9), and R⁷ is not H forgroup 6);

optionally, when R⁶ and R⁷ are bound to the same nitrogen, R⁶ and R⁷together with the nitrogen to which they are bound, form a 5 to 7membered heterocycloalkyl ring which optionally contains O, NR⁶, orS(O)_(t) wherein t is 0, 1 or 2;

optionally, when R⁷ and R¹² are bound to the same nitrogen, R⁷ and R¹²together with the nitrogen to which they are bound, form a 5 to 7membered heterocycloalkyl ring which optionally contains O, NR⁶, orS(O)_(t) wherein t is 0, 1 or 2;

R⁹⁵ and R¹⁵ are independently H, C₁ -C₄ alkyl or arylalkyl;

R¹⁴ is C₁ -C₄ alkyl, aryl or arylalkyl;

n=0, 1, 2, 3 or 4; and

t=0, or 2;

or pharmaceutically acceptable salts thereof.

This invention also provides a method for inhibiting tumor growth byadministering an effective amount of the tricyclic compounds, describedherein, to a mammal (e.g., a human) in need of such treatment. Inparticular, this invention provides a method for inhibiting the growthof tumors expressing an activated Ras oncogene by the administration ofan effective amount of the above described compounds. Examples of tumorswhich may be inhibited include, but are not limited to, lung cancer(e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreaticcarcinoma such as, for example, exocrine pancreatic carcinoma), coloncancers (e.g., colorectal carcinomas, such as, for example, colonadenocarcinoma and colon adenoma), myeloid leukemias (for example, acutemyelogenous leukemia (AML)), thyroid follicular cancer, myelodysplasticsyndrome (MDS), bladder carcinoma and epidermal carcinoma.

It is believed that this invention also provides a method for inhibitingproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes--i.e., the Ras gene itself is not activated by mutation to anoncogenic form--with said inhibition being accomplished by theadministration of an effective amount of the tricyclic compoundsdescribed herein, to a mammal (e.g., a human) in need of such treatment.For example, the benign proliferative disorder neurofibromatosis, ortumors in which Ras is activated due to mutation or overexpression oftyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may beinhibited by the tricyclic compounds described herein.

The compounds of this invention inhibit farnesyl protein transferase andthe farnesylation of the oncogene protein Ras. This invention furtherprovides a method of inhibiting ras farnesyl protein transferase, inmammals, especially humans, by the administration of an effective amountof the tricyclic compounds described above. The administration of thecompounds of this invention to patients, to inhibit farnesyl proteintransferase, is useful in the treatment of the cancers described above.

The tricyclic compounds useful in the methods of this invention inhibitthe abnormal growth of cells. Without wishing to be bound by theory, itis believed that these compounds may function through the inhibition ofG-protein function, such as ras p21, by blocking G-proteinisoprenylation, thus making them useful in the treatment ofproliferative diseases such as tumor growth and cancer. Without wishingto be bound by theory, it is believed that these compounds inhibit rasfarnesyl protein transferase, and thus show antiproliferative activityagainst ras transformed cells.

DETAILED DESCRIPTION OF THE INVENTION

All of the publications cited herein are hereby expressly incorporatedin their entirety by reference.

As used herein, the following terms are used as defined below unlessotherwise indicated:

"MS" represents Mass Spec;

"MH+" represents the molecular ion plus hydrogen of the molecule in themass spectrum;

"Bu" represents butyl;

"Et" represents ethyl;

"Tr" represents trityl, (i.e., triphenylmethyl);

"Me" represents methyl;

"Ph" represents phenyl;

"BOC" represents t-butoxycarbonyl;

"FMOC" represents 9-fluorenylmethoxycarbonyl;

"alkyl" (including the alkyl portions of alkoxy, alkylamino anddialkylamino) represents straight and branched carbon chains andcontains from one to twenty carbon atoms, preferably one to six carbonatoms; said alkyl group optionally being substitued with one, two orthree groups independently selected from hydroxy, alkoxy, halo (e.g.,--CF₃), amino, alkylamino, dialkylamino, N-acylalkylamino,N-alkyl-N-acylamino, or --S(O)_(m) -alkyl (wherein m is 0, 1 or 2), andwherein the alkyl portion of said optional groups are as defined above;

"alkenyl" represents straight and branched carbon chains having at leastone carbon to carbon double bond and containing from 2 to 12 carbonatoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to6 carbon atoms;

"alkynyl" represents straight and branched carbon chains having at leastone carbon to carbon triple bond and containing from 2 to 12 carbonatoms, preferably from 2 to 6 carbon atoms;

"aralkyl" represents an alkyl group, as defined above, wherein one ormore hydrogen atoms of the alkyl moiety have been replaced by one ormore aryl groups, as defined below (e.g., benzyl and diphenylmethyl);

"aryl" (including the aryl portion of aryloxy and aralkyl) represents amonocyclic, bicyclic or tricyclic carbocyclic group containing from 6 to15 carbon atoms and comprising at least one aromatic ring, such asphenyl, naphthyl, phenanthryl, tetrahydronaphthyl or indanyl, with allavailable substitutable carbon atoms of the carbocyclic group beingintended as possible points of attachment, said carbocyclic group beingoptionally substituted with one or more, preferably 1 to 3,substituents, independently selected from: (1) halo, (2) alkyl (e.g., C₁to C₆ alkyl), (3) hydroxy, (4) alkoxy (e.g., C₁ to C₆ alkoxy), (5) --CN,(6) phenyl, (7) phenoxy, (8) --CF₃, (9) amino, (10) alkylamino, (11)dialkylamino, (12) aryl, (13) aralkoxy, (14) aryloxy, (15) --S(O)_(m)-aryl (wherein m is 0, 1, or 2), (16) --COOR⁶⁰ (R⁶⁰ is as definedabove), (17) --NO₂, or (18) substituted C₁ -C₆ alkyl wherein said alkylgroup is substituted with 1, 2, or 3 groups independently selected from(a) amino, (b) alkylamino, (c) dialkylamino, (d) aryl, (e)N-acylalkyl-amino, (f) N-alkyl-N-acylamino, (g) N-aralkyl-N-acylamino,(h) hydroxy, (i) alkoxy, (j) halo (e.g., CF₃), or (k) heterocycloalkyl,provided that when there are two or more hydroxy, amino, alkylamino ordialkylamino substituents on the substituted C₁ -C₆ alkyl group, thesubstituents are on different carbon atoms; or alternatively said arylgroup may be fused through adjacent atoms to form a fused ringcontaining up to four carbon and/or heteroatoms (e.g., methylenedioxyphenyl, indanyl, tetralinyl, dihydrobenzofuranyl);

"aralkoxy"--represents an aralkyl group, as defined above, in which thealkyl moiety is covalently bonded to an adjacent structural elementthrough an oxygen atom, for example, benzyloxy;

"aryloxy"--represents an aryl group, as defined above, covalently bondedto an adjacent structural element through an oxygen atom, for example,phenoxy;

"arylthio"--represents an aryl group, as defined above, covalentlybonded to an adjacent structural element through a sulfur atom, forexample, phenylthio;

"cycloalkyl" represents a saturated or unsaturated nonaromaticcarbocyclic ring of from 3 to 8 carbon atoms, preferably 3 to 6 carbonatoms;

"halo" represents fluoro, chloro, bromo and iodo;

"heterocycloalkyl" represents a saturated or unsaturated nonaromaticcarbocyclic ring containing from 3 to 15 carbon atoms, preferably from 4to 6 carbon atoms, and from 1 to 3 heteroatoms selected from O, S, --SO₂-- or NR⁹⁵ (suitable heterocycloalkyl groups include tetrahydrofuranyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, piperidinyl,pyrrolidinyl, piperazinyl, dioxanyl, morpholino,diaza-2,2,2-bicyclooctane etc.), wherein any of the availablesubstitutable carbon and nitrogen atoms in the ring are optionallysubstituted with one, two, three or more groups independently selectedfrom C₁ -C₆ alkyl, aryl, aralkyl, haloalkyl, amino, alkylamino,dialkylamino, --S(O)_(m) -aryl (wherein m is 0, 1 or 2 and aryl isdefined above), --C(O)R⁹ (wherein R⁹ is defined above) or an acylradical of a naturally occuring amino acid; and

"heteroaryl" (including the heteroaryl portion of heteroarylalkyl)represents a monocyclic, bicyclic or tricyclic group containing from 2to 14 carbon atoms and comprising one or more, (preferably 1 to 3),heteroatoms selected from O, S or N, said heteroatoms interrupting acarbocyclic ring structure and having a sufficient number of delocalizedpi electrons to provide aromatic character, such as triazolyl, pyridyl,imidazolyl, thienyl, furanyl, imidazolyl, quinolyl, isoquinolyl,benzofuranyl, benzopyranyl, benzothienyl, thiazolyl, indolyl,naphthyridinyl, or pyridyl N-oxide, wherein pyridyl N-oxide can berepresented as: ##STR13## with all available substitutable carbon andheteroatoms of the cyclic group being intended as possible points ofattachment, said cyclic group being optionally substituted with 1, 2, 3or more groups independently selected from halo, alkyl, aryl, aralkyl,heteroaryl, hydroxy, alkoxy, phenoxy, --NO₂, --CF₃, amino, alkylamino,dialkylamino, and --COOR⁶⁰ wherein R⁶⁰ is as defined above (e.g.,benzyl).

As used herein, the term "tertiary amine base" means DMAP, pyridine or atrialkylamine, such as Et₃ N or Hunigs base; and

"hydride reducing agent" means a metal hydride reagent, such as NaBH₄,Red-Al, DIBAL-H, L-Selectride, Vitride, LiBH₄, LiAlH₄, LiAl(OtBu)₃ H,NaCNBH₃, DMAB, zinc borohydride, calcium borohydride, sodiumtriacetoxyborohydride, a combination of LiBH₄ and ZnBr₂, or acombination of NaBH₄ and LiCl.

The term "acyl radical of a naturally occurring amino acid" means agroup of the formula --C(O)--R²⁹, wherein R²⁹ is a group of the formula##STR14## wherein R³⁰ and R³¹ are the residual portions of said aminoacid. For example R³⁰ and R³¹ can be independently selected from H,alkyl or M-substituted alkyl, wherein M is HO--, HS--, CH₃ S--, --NH₂,phenyl, p-hydroxyphenyl, imidazolyl or indolyl, such that HO--C(O)--R²⁹is an amino acid selected from alanine, glycine, valine, leucine,isoleucine, phenylalanine, tryptophan, methionine, serine, threonine,histidine, cysteine or tyrosine.

The following solvents and reagents are referred to herein by theabbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol(MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc);N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroaceticanhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid(MCPBA); triethylamine (Et₃ N); diethyl ether (Et₂ O); ethylchloroformate (ClCO₂ Et); 1-(3-dimethylaminopropyl)-3-ethyl carbodiimdehydrochloride (DEC); N,N'-carbonyldiimidazole (CDI); 1,8-diaza-bicyclo5.4.0!undec-7-ene (DBU);O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU); tetrabuytlammonium fluoride (TBAF);dicyclohexylcarbodiimide (DCC); N,N-dimethylamino-pyridine (DMAP);diisopropylethylamine (Hunigs base);2-(t-butoxy-carbonyloxyimino)-2-phenylacetonitrile! (BOC-ON);9-fluorenylmethyl chloroformate (FMOC-Cl); sodiumbis(2-methoxyethoxy)aluminum hydride (Red-Al); diisobutyl-aluminumhydride (DIBAL-H); lithium tri-sec-butylborohydride (L-selectride);dichloromethane (DCM); diisopropylcarbodiimide (DIC); andN,N-dimethylacetamide (DMA).

Lines drawn into the ring systems indicate that the indicated bond maybe attached to any of the substitutable ring carbon atoms.

Certain compounds of the invention may exist in different isomeric(e.g., enantiomers, diastereoisomers or geometric isomers) forms. Forexample, compounds of the formula (1.0) wherein X is CH or N can have achiral center at C11 of the tricyclic portion of the molecule, which C11carbon can have the S or R absolute configuration, and varioussubstituent groups, e.g. R¹, R², can also comprise chiral centers. Theinvention contemplates all such isomers both in pure form and inadmixture, including racemic mixtures. In the particular case ofcompounds of formula (1.0) where R² is other than H, the carbon atom towhich said R² group is attached can exist in the R or S configuration.While only one configuration is generally shown for such compounds offormula (1.0), the invention contemplates all such isomers both in pureform and in admixture, including racemic mixtures. Enol forms are alsoincluded, as are both the E and Z isomers of compounds containing adouble bond, (e.g. compounds wherein R² is an alkenyl group).

Certain tricyclic compounds will be acidic in nature, e.g. thosecompounds which possess a carboxyl or phenolic hydroxyl group. Thesecompounds may form pharmaceutically acceptable salts. Examples of suchsalts may include sodium, potassium, calcium, aluminum, gold and silversalts. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

Certain basic tricyclic compounds also form pharmaceutically acceptablesalts, e.g., acid addition salts and quaternary salts. For example, thepyrido-nitrogen atoms may form salts with strong acid, while compoundshaving basic substituents such as amino groups also form salts withweaker acids. Examples of suitable acids for salt formation arehydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonicand other mineral and carboxylic acids well known to those in the art.The salts are prepared by contacting the free base form with asufficient amount desired acid to produce a salt in the conventionalmanner. The free base forms may be regenerated by treating the salt witha suitable dilute aqueous base solution such as dilute aqueous NaOH,potassium carbonate, ammonia and sodium bicarbonate. The free base formsdiffer from their respective salt forms somewhat in certain physicalproperties, such as solubility in polar solvents, but the acid and basesalts are otherwise equivalent to their respective free base forms forpurposes of the invention.

All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Those skilled in the art will appreciate that when x in formula 82.0 isgreater than 1 (e.g., 2, 3, 4, 5 or 6) each R^(a) and each R^(b) isindependently selected for each carbon to which they are bound. Thus,each R^(a) and R^(b) on adjacent carbons can be the same or different.

Examples of R¹, wherein R¹ is a group of formula (82.0), includecompounds of group D, wherein D is --C(O)--CH₂ --R⁵, --C(O)--O--R⁵ or--C(O)--NH--R⁵, wherein R⁵ is pyridyl, pyridyl N-oxide, ##STR15## or apiperidinyl group of the formula ##STR16## wherein R¹¹ represents H, C₁-C₆ alkyl, haloalkyl or --C(O)--R⁹ wherein R⁹ is C₁ -C₆ alkyl, C₁ -C₆alkoxy or --NH(R¹⁰) wherein R¹⁰ is H or alkyl, or the group --C(O)--R⁹represents an acyl radical of a naturally occurring amino acid.

R¹ substituents include those substituents for formula (82.0) wherein:

(a) T is selected from --C(O)--, --SO₂, or --C(O)--C(O)--;

(b) x is 0, 1, or 2 (e.g., 0 or 1);

(c) R^(a) and R^(b) are independently selected from: (1) H; (2)NH{C(O)}_(z) R⁶⁰ wherein z is 0 or 1 (e.g., z is 1), and R⁶⁰ is alkyl(e.g., methyl); (3) --(CH)_(w) S(O)_(m) R⁶⁰ wherein w is 0, 1, 2 or 3(e.g., w is 0, 1, or 2, for example w is 2), m is 0, 1 or 2 (e.g., 0 or2), and R⁶⁰ is alkyl (e.g., methyl); (4) alkyl (e.g., methyl); or (5) C₁-C₆ alkoxy (e.g., --OCH₃); or R^(a) and R^(b) taken together representcycloalkyl (e.g., cyclopentyl or cyclopropyl), or ═O; and

(d) R⁹² is selected from (1) H; (2) aryl (e.g., phenyl or naphthyl); (3)substituted aryl, for example, aryl having substituents independentlyselected from (i) alkoxy (e.g., --OCH₃), (ii) methylenedioxy, (iii)aralkoxy (e.g., benzyloxy), (iv) aryloxy (e.g., phenoxy--i.e., C₆ H₅O--), (v) alkyl (e.g., --CH(CH₃)₂), (vi) halo (e.g., Cl), (vii) aryl(e.g., phenyl) or (viii) alkyl substituted with a heterocycloalkyl ring##STR17## (4) aralkyl (e.g., benzyl and diphenylmethyl); (5) aryloxy(e.g., phenoxy); (6) arylthio (e.g., C₆ H₅ S--); (7) alkyl (e.g.,methyl); (8) heteroaryl (e.g., pyridyl N-oxide, indolyl, thienyl,quinolinyl, benzothienyl and pyridyl); (9) substituted heteroaryl, forexample, heteroaryl having substituents independently selected from (i)aryl (e.g., phenyl), (ii) alkyl (e.g., methyl), (iii) alkoxy (e.g.,methoxy), (iv) amino (e.g., --NH₂), or (v) aralkyl (e.g., benzyl); (10)substituted heterocycloalkyl, for example, heterocycloalkyl havingsubstituents independently selected from (i) aryl (e.g., phenyl) or (ii)--S(O)_(m) -aryl wherein (e.g., m is 2 and aryl represents phenylsubstitued with methyl); or (11) substituted alkyl, for example, alkylhaving substituents independently selected from --S(O)_(m) -alkylwherein m is 0, 1, or 2 (e.g., ethyl substitued with --SO₂ CH₃ or--SCH₃).

Examples of substituted aryl groups for R⁹² include methoxyphenyl,dimethoxyphenyl (i.e., (CH₃ O)₂ C₆ H₄), methylenedioxyphenyl,benzyloxyphenyl, phenoxyphenyl (i.e., C₆ H₅ OC₆ H₄), C₆ H₄ CH(CH₃)₂,chlorophenyl, dichlorophenyl, and phenylphenyl (i.e., biphenyl, C₆ H₅ C₆H₄).

Examples of substituted heteroaryls for R⁹² include thiazole substitutedwith a phenyl group and a methyl group, thiazole substituted with --NH₂and indole substituted at the nitrogen with benzyl.

Examples of substituted heterocycloalkyl groups for R⁹² include thesubstituent: ##STR18##

Preferably, R¹ is selected from: (1) a group of the formula --C(O)--CH₂--R⁵ wherein R⁵ is ##STR19## wherein R¹¹ is --C(O)--R⁹, R⁹ is --NH(R¹⁰)and R¹⁰ is H, for example, R⁵ is a group of the formula ##STR20## (2) agroup of formula (82.0) wherein T is --C(O)--, x is 1 or 2 and R⁹² isaryl (preferably phenyl) or heteroaryl (preferably pyridyl or pyridylN-oxide, e.g., 3- or 4- pyridyl or 3- or 4- pyridyl N-oxide).

Examples of R¹, wherein R¹ is a group of formula (82.0), also includegroups of the formula: ##STR21##

Examples of R¹, wherein R¹ is a group of formula (82.0), also includegroups of the formula: ##STR22##

Examples of R¹ also include groups selected from: ##STR23##

Examples of R² groups include: (1) --C(O)NR⁶ R⁷ (for example see formula84.0 below), and (2) substituted alkyl wherein the substituent is--C(O)NR⁶ R⁷ (e.g., --CH₂ C(O)NR⁶ R⁷, for example, see formula 86.0below). Examples of R⁶ and R⁷ for these groups include: (1) H; (2)substituted alkyl, for example, alkyl having substituents independentlyselected from (i) --CN, (ii) cycloalkyl (e.g., cyclopropyl andcyclohexyl), (iii) alkoxy (e.g., methoxy), (iv)-S-alkyl (e.g., --SCH₃),(iv) aryl (e.g., phenyl and naphthyl), (v) substituted aryl (e.g.,chlorophenyl, nitrophenyl and methoxyphenyl), (vi) heterocycloalkyl(e.g., tetrahydrofuranyl), (vii) methylenedioxyphenyl, (viii)--O-alkyl-O-alkyl (e.g., --O(CH₂)₂ OCH₃); (3) alkyl (e.g., methyl,isopropyl, --CH₂ CH(CH₃)₂, and n-butyl), (4) cycloalkyl (e.g.,cyclopropyl), (5) heteroarylalkyl (e.g., --CH₂ -pyridyl, --(CH₂)₃-imidazolyl, --CH₂ -thienyl, and --CH₂ -furanyl), and (6) aralkylwherein said aryl group is substituted (e.g., --(CH₂)₂ C₆ H₄ OCH₃ and--(CH₂)₂ C₆ H₄ (OCH₃)₂).

Examples of substituted alkyl groups for the above R⁶ and R⁷ groupsinclude: --(CH₂)₂ CN, --CH₂ -cyclopropyl, --(CH₂)₂ OCH₃, --(CH₂)₃ OCH₃,--(CH₂)₂ SCH₃, --CH₂ CH(C₆ H₅)₂, --(CH₂)₂ C₆ H₅, --(CH₂)₄ C₆ H₅, --CH₂C₆ H₅, --CH₂ -naphthyl, --(CH₂)₂ C₆ H₄ Cl, --CH₂ C₆ H₄ Cl, --CH₂-tetrahydrofuranyl, --CH₂ -cyclohexyl, --(CH₂)₃ O(CH₂)₂ OCH₃, ##STR24##and --CH₂ -nitrophenyl.

Preferably, R² is selected from --C(O)NR⁶ R⁷ or --CH₂ C(O)NR⁶ R⁷wherein, preferably, R⁶ and R⁷ are independently selected from H, alkyl,cycloalkyl, heteroarylalkyl or heteroaryl, and most preferably R⁶ and R⁷are independently selected from H, alkyl, cycloalkyl or heteroarylalkyl.

Examples of R² include groups having the formula: ##STR25## wherein R⁶⁵in formulas (84.0) and (86.0) are selected from: ##STR26##

Examples of R² groups also include: (1) alkyl, (2) substitued alkyl, forexample, alkyl having substituents independently selected from (i) aryl,(ii) --OR⁶, (iii) --S(O)_(t) R⁶, and (iv) --N(R⁶)--C(O)R⁷ ; and (3)--C(O)OR⁶. Examples of such R² groups include the groups: CH₃ (CH₂)₃ --,C₆ H₅ CH₂ --, CH₃ O(CH₂)₂ --, CH₃ S(CH₂)₂ --, CH₃ O(CH₂)₃ --, n-C₃ H₇O(CH₂)₂ --, CH₃ CONH(CH₂)₄ --, --CH₂ OH, --C(O)OC₂ H₅, ##STR27##

Examples of R² groups also include ##STR28##

Those skilled in the art will recognize that the disulfide dimers for R¹can be represented by the formulas: ##STR29##

Certain compounds of the formula (1.0) comprise sulfhydryl groups,(i.e., --CH₂ SH), which sulfhydryl groups are capable of reacting toform disulfide bonds resulting in dimeric compounds. An example of suchdimers are disulfides of the formula (Ia). Said sulfhydryl groups canalso form disulfides with other thiols such as glutathione. Disulfidesincluding but not limited to disulfides of formula (Ia) are within thescope of the invention and are encompassed by the structure of formula(1.0). ##STR30##

Compounds of the formula (1.0) can generally be prepared from an amineof the formula (2.0) as shown in Reaction Scheme 1. ##STR31##

For compounds of the formula (1.0) wherein R¹ and the nitrogen atom towhich it is attached together comprise an amide, e.g. where R¹ is--C(O)--CH₂ --R⁵, the amine (2.0) is reacted with a carboxylic acid ofthe formula R²⁰ --C(O)--OH, wherein R²⁰ --C(O)-- is R¹, in the presenceof a coupling agent such as DEC, CDI or DCC. The reaction is typicallycarried out in a suitable organic solvent such as DMF, THF or CH₂ Cl₂ ata temperature of -10° to 100° C., preferably at 0° to 50° C., and mostpreferably at about room temperature. When the coupling agent is DCC orDEC, the reaction is preferably conducted in the presence of HOBT andN-methylmorpholine.

Alternatively, the amine (2.0) can be reacted with a compound of theformula R¹ -L, wherein R¹ is as defined above and L is a leaving group,such as Cl, Br, I, --O--C(O)--R⁴⁰ wherein R⁴⁰ is C₁ -C₆ alkyl or phenyl,or a sulfonate group of the formula --OSO₂ --R²⁰, wherein R²⁰ isselected from C₁ -C₆ alkyl, phenyl, CF₃, tolyl and p-bromophenyl, toform a compound of the formula (1.0). The reaction is carried out in thepresence of a base, preferably a tertiary amine base, such as Et₃ N,DMAP, pyridine or Hunigs base.

Compounds of Formula 1.0 wherein: R¹ is --C(O)--CH₂ --R⁵, R⁵ is apiperidine of the formula: ##STR32## R¹¹ represents --C(O)--R⁹, R⁹ is--NH(R¹⁰) and R¹⁰ is H (i.e., a carboxamide) can be made by reacting acompound of Formula 1.0, wherein R¹ is --C(O)--CH₂ --R⁵ and R⁵ is theabove described piperidine wherein R¹¹ is H, with an excess of urea inwater. This reaction can be run with about 4 to about 10 equivalents ofurea relative to the unsubstitued piperidine starting reactant.Generally, about 10 equivalents of urea can be used. The reaction is runfor about 3 to about 68 hours. Generally, the reaction can be run forabout 60 to 70 hours. The reaction is usually run at the refluxtemperature of the reaction mixture. This can range from about 98 toabout 100° C. The amount of the unsubstitued piperidine startingreactant relative to water may typically vary from about 0.025 g/ml toabout 0.6 g/ml, and can generally be about 0.1 g/ml.

For preparing compounds of the formula (1.0) wherein R¹ and the nitrogenatom to which it is attached together comprise an amine, e.g. where R¹is a group of the formula ##STR33## the amine (2.0) is reacted with analdehyde of the formula R²¹ --CHO, wherein R²¹ is selected such that R¹corresponds to R²¹ --CH₂ --, e.g. an aldehyde of the formula ##STR34##to form an imine of the formula (3.0), wherein R²¹ is as defined above,as shown in Reaction Scheme 2. The --NH₂ and --SH groups of suchaldehydes are typically protected, e.g. as the N-BOC and S-Tr groups,respectively. The imine (3.0) is reduced under suitable reactionconditions to form a compound of the formula (1.0). Preferably thereduction is carried out using a hydride reducing agent, such as sodiumtriacetoxyborohydride or NaCNBH₃, preferably in the presence ofmolecular sieves. ##STR35##

When conducting the reactions described above, where R¹ comprises achemically reactive group, such as amine thiol group, such groups mustgenerally be protected with a suitable protecting group, which can laterbe removed to complete the synthesis of a compound of formula (1.0). Forexample, amines can preferably be protected with the BOC protectinggroup, while thiols can be protected with the trityl (i.e.,triphenylmethyl) protecting group. Deprotection, i.e., the removal ofthese protecting groups is then generally the final step in thesynthesis of such compounds of formula (1.0).

For preparing compounds of the formula (1.0) wherein R¹ is--C(O)--NH--R⁵, a compound of the formula (2.0) is reacted with anisocyanate of the formula R⁵ --N═C═O, in a suitable solvent such as DMF,THF or CH₂ Cl₂ using methods well known in the art.

Alternatively, an amine (2.0) is reacted with phosgene to form achloroformate intermediate of the formula (4.0), as shown in ReactionScheme 3. The chloroformate (4.0) is generally not isolated and isreacted with an amine of the formula R⁵ --NH₂, wherein R⁵ is as definedabove, to form a compound of the formula (1.0), wherein R¹ is--C(O)--NH--R⁵. ##STR36##

Compounds of the formula (1.0) wherein R¹ is --C(O)--O--R⁵ can beprepared by reacting a compound of the formula (2.0) with achloroformate of the formula R⁵ --O--C(O)Cl, wherein R⁵ is as definedabove, in the presence of a base, such as a tertiary amine base, to forma compound of formula (1.0). Alternatively, a compound (1.0) wherein R¹is --C(O)--O--R⁵ can be prepared by reacting a compound of formula (4.0)with an alcohol of the formula R⁵ --OH

Certain compounds of formula (1.0) can be converted to other compoundsof the formula (1.0) using standard reaction conditions. For example,compounds of the formula (1.0) wherein R² is --CO₂ H, (i.e., --C(O)OR⁶and R⁶ is H), can be prepared by ozonolysis of a compound of formula(1.0) wherein R² is CH₂ ═CH--, followed by oxidation of the resultingaldehyde.

Compounds of the formula (1.0) wherein R² is --C(O)OR⁶, where R⁶ isother than H, can be prepared from a compound of the formula (1.0)wherein R² is --CO₂ H by treating with SOCl₂ or oxalyl chloride, thenwith an alcohol of the formula R⁶ OH, wherein R⁶ is as defined above.Similarly, compounds of formula (1.0) wherein R² is --C(O)NR⁶ R⁷ can beprepared from a compound of the formula (1.0) wherein R² is --CO₂ H viaessentially the same method but substituting an amine of the formula R⁶R⁷ NH for the alcohol R⁶ OH. Alternatively, compounds of formula (1.0)wherein R² is --C(O)NR⁶ R⁷ can be prepared by reacting a compound of theformula (1.0) wherein R² is --CO₂ H with an amine R⁶ R⁷ NH in thepresence of a coupling agent, such as DCC or DEC.

In an analogous manner, compounds of formula (1.0) wherein R² is alkylsubstituted by a group of the formula --C(O)OR⁶ or --C(O)NR⁶ R⁷ can beprepared via substantially the same procedures as described above toform compounds wherein R² is --CO₂ H, --C(O)OR⁶ or --C(O)NR⁶ R⁷, byreplacing the compound of formula (1.0) wherein R² is CH₂ ═CH-- with anappropriate alkenyl group, (i.e., a group of the formula --(CH₂)_(p)--CH═CH₂, wherein p is 1, 2, 3, 4, etc.).

Compounds of the formula (1.0) wherein R² contains a substituent offormula --S(O)_(t) R⁶, wherein t=1 or 2, can be prepared by oxidation ofan analogous compound of the formula (1.0) wherein R² contains asubstituent of formula --S(O)_(t) R₆, wherein t=0, using a suitableoxidizing agent, such as a peracid, preferably MCPBA.

One skilled in the art will recognize that the above transformationsmay, in certain instances, such as where R¹ is a group of the formula##STR37## require that the oxidation be carried out prior tointroduction of the R¹ group to formula (1.0).

Amines of the formula (2.0) can be prepared in optically active formusing appropriate chiral starting materials or alternatively can beprepared using racemic starting compounds to give a mixture ofstereoisomeric compounds which can then be separated by resolution orchiral HPLC to give the desired compound (2.0). For example, compounds(2.0) and (2.10) are stereoisomeric amines which can be separated byclassical resolution techniques using a suitable resolving agent, suchas a chiral acid. Chiral acid resolving agents are well known in the artand include such compounds as D- or L-malic acid, D- or L-tartaric acid,di-p-toluoyl-D-tartaric acid, di-p-toluoyl-L-tartaric acid,di-benzoyl-D-tartaric acid and di-benzoyl-L-tartaric acid.Alternatively, the stereoisomeric amines (2.0) and (2.10) could beseparated using a chiral HPLC column via standard methods. ##STR38##

For example, in the case of compounds of the formula (2.0) and (2.10)wherein X is N or CH, at least four stereoisomers of said compounds canexist, i.e., compounds of formula (2.20), (2.21), (2.22) and (2.23).##STR39## Diastereomers, such as compounds (2.20) and (2.22), or (2.21)and (2.23) can typically be separated using conventional methods, suchas chromatography. Resolution methods are required for separation ofenantiomers, such as compounds (2.20) and (2.21), or (2.22) and (2.23).

Amines of the formula (2.1), i.e., an amine of the formula (2.0) whereinX is N, can be prepared from a piperazine derivative of the formula(5.0), wherein R² is as defined above, and a compound of the formula(6.0), wherein L is a leaving group as defined above and A, B, W and Zare as defined above, via the process shown in Reaction Scheme 4.##STR40##

In the process of Reaction Scheme 4, the piperazine (5.0) is reactedwith compound (6.0) in the presence of a base, such as a tertiary aminebase, to form a compound of the formula (7.0). Compound (7.0) is thenhydrolyzed using a suitable acid, such as TFA, HCl or H₂ SO₄, in asolvent such as dioxane or CH₂ Cl₂, to form the amine (2.1).

Amines of the formula (2.2), i.e., an amine of the formula (2.0) whereinX is C or CH, can be prepared by hydrolysis of a carbamate compound ofthe formula (8.0), wherein R²² is C₁ -C₆ alkyl, preferably ethyl ort-butyl, and R², A, B, W and Z are as defined above. The hydrolysis iscarried out using a suitable acid, such as HCl, in a solvent such asdioxane. ##STR41##

Amines of the formula (2.3), i.e., an amine of the formula (2.0) whereinX is CH, can be prepared by reduction of an amine of the formula (2.4),i.e., an amine of the formula (2.0) wherein X is C. The reduction istypically carried out using a suitable reducing agent, such as DIBAL-Hor LiAlH₄, in a solvent such as THF or toluene, preferably at atemperature of 30° to 100° C. ##STR42##

Carbamates of the formula (8.0) can be prepared by reacting a N-methylcompound of the formula (9.0) wherein X is C or CH, and A, B, W and Zare as defined above, with an alkyl chloroformate of the formula R²²OC(O)Cl, wherein R²² is C₁ -C₆ alkyl, preferably ethyl, followingsubstantially the same procedures as described in U.S. Pat. Nos.4,282,233 and 4,335,036. ##STR43##

Compounds of the formula (9.1), i.e., a compound of the formula (9.0)wherein X is C, can generally be prepared via methods disclosed in U.S.Pat. No. 3,326,924, and in PCT International Publications WO/92/20681and WO93/02081. ##STR44##

Compounds of the formula (9.1) can be prepared from a Grignard reagentof the formula (12.0) and a ketone of the formula (14.0), wherein A, B,W and Z are as defined above, via the process shown in Reaction Scheme5. ##STR45##

In the process of Reaction Scheme 5, the Grignard reagent (12.0) isreacted with the ketone (14.0) to form a compound of the formula (15.0).The reaction is generally performed under anhydrous conditions in aninert solvent, such as THF, Et₂ O or toluene, at a temperature of 0° to75° C., with hydrolysis of the resulting intermediate, typically usingan aqueous acid, such as aqueous HCl, to form the alcohol (15.0).Alternatively, another organometallic reagent can be used in place ofthe Grignard reagent, such as an organolithium reagent, (i.e., acompound of formula (12.0) wherein MgX¹ is replaced by Li).

Compound (15.0) is dehydrated, e.g. by treating with an acid, such as H₂SO₄, to form a compound of the formula (9.1).

Ketones of the formula (14.0) are known or can be prepared by theprocedures described in J. Med. Chem., 4238 (1992), U.S. Pat. No.5,089,496, and in PCT International Publications WO92/20681 andWO93/02081. For example, intramolecular cyclization of a nitrile offormula (11.0), as defined below, using a strong acid, such as CF₃ SO₃H, at a temperature of -15° to 100° C., to form an imine intermediatewhich is hydrolyzed with water or aqueous acid to form the ketone(14.0). ##STR46##

Alternatively, intramolecular Friedel-Crafts acylation of an acidchloride of formula (16.0) may also provide the desired ketone offormula (14.0). The reaction may be carried out under usualFriedel-Crafts conditions in an inert solvent and in the presence of aLewis acid such as aluminum chloride. ##STR47##

Ketones of the formula (14.1), i.e., a compound of the formula (14.0)wherein W is CH, can be prepared by heating a compound of the formula(14.3), i.e., a compound of formula (14.0) wherein W is CH₂, with SeO₂in acetic acid. ##STR48##

Acid chlorides of formula (16.0) can be obtained by hydrolysis of acompound of formula (11.0) to the corresponding carboxylic acidtypically by heating with an aqueous acid (e.g., aqueous HCl), followedby conversion of the acid to the acid chloride of (16.0) under standardconditions well known to those skilled in the art (e.g., by treatingwith SOCl₂ or oxalyl chloride).

Compounds of the formula (11.1), i.e., compounds of the formula (11.0)wherein W is CH₂, are known or can generally be prepared by the processshown in Reaction Scheme 6. According to the process of Reaction Scheme6 a solution of a compound of the formula (17.0), wherein A is asdefined above, in t-butanol is heated in the presence of concentrated H₂SO₄ to form a t-butylamide of the formula (18.0). The t-butylamide(18.0) is reacted with an alkyllithium reagent, such as n-butyllithium,at -100° to 0° C., preferably at -60° to -20° C., then treated with NaBrand a benzyl halide of formula (19.0), wherein X¹ is Cl, Br or I, and Bis as defined above, to form a compound of the formula (41.0). Compound(41.0) is treated with POCl₃ in a suitable solvent, such as toluene at30° to 120° C., preferably at reflux, to form compound (11.1). ##STR49##

Compounds of the formula (9.1) can also be prepared by cyclizing aketone of the formula (10.0), wherein R², A, B, Z and W are as definedabove. The cyclization is conducted by treating compound (10.0) with asuper acid, such as HF/BF₃, CF₃ SO₃ H or CH₃ SO₃ H/BF₃. The reaction canbe performed neat or in the presence of a suitable inert solvent such asCH₂ Cl₂. Where HF/BF₃ is used for cyclization, the reaction is generallycarried out at -60° to 10° C., preferably at -50° to 5° C., and thereaction time is controlled to minimize side reactions caused byreaction of HF with the product (9.1). Where the super acid is CF₃ SO₃H, the reaction is typically carried out at 25° to 150° C., preferablyat 40° to 120° C. An excess of super acid is generally used, typically1.5 equiv. to 30 equiv. ##STR50##

Compounds of the formula (10.0) can be prepared by reacting a compoundof the formula (11.0), wherein A, B, Z, and W are as defined above, witha Grignard reagent of the formula (12.0), wherein X¹ is Cl, Br or I, andR² is as defined above. The reaction is generally performed underanhydrous conditions in an inert solvent, such as THF, Et₂ O or toluene,at a temperature of 0° to 75° C., with hydrolysis of the resultingintermediate, typically using an aqueous acid, such as aqueous HCl, toform the ketone (10.0). Alternatively, another organometallic reagentcan be used in place of the Grignard reagent, such as an organolithiumreagent. ##STR51##

The Grignard reagent (12.0) can be prepared from the corresponding halocompound (13.0), wherein X¹ is Cl, Br or I, and R² is as defined above,using Mg metal via standard procedures known in the art. Similarly, theanalogous organolithium compounds can be prepared from the halides(13.0) via standard methods, e.g. via transmetallation using analkyllithium compound, such as t-butyllithium. ##STR52##

Amines of the formula (2.5), wherein X² is Br or I, (i.e., amines of theformula (2.0) wherein A is Br or I, and X is CH or C), can be preparedvia the process shown in Reaction Scheme 7. ##STR53##

In Step A of Reaction Scheme 7, a compound of the formula (8.1), i.e., acompound of formula (8.0) wherein A is H, is reacted with atetraalkylammonium nitrate, such as tetrabutylammonium nitrate, and TFAAin a suitable solvent, such as CH₂ Cl₂, at -30° to 20° C., preferably atabout 0° C., to form a compound of the formula (20.0), wherein R²², B,W, Z and R² are as defined above.

In Step B, compound (20.0) is heated with a suitable reducing agent,such as a combination of Fe and CaCl₂, in a polar solvent, such as a C₁-C₄ alcohol, preferably EtOH, at a temperature of 40° to 100°,preferably at 50° to 80° C., to form a compound of formula (21.0),wherein R²², B, W, Z and R² are as defined above.

In Step C, compound (21.0) is converted to the halide (8.2), wherein X²is Br or I, and R²², B, W, Z and R² are as defined above. For forming acompound of formula (8.2) wherein X² is Br, compound (21.0)is treatedwith Br₂ and HBr at a temperature of -30° to 15° C., preferably at -10°to 10° C., to form the bromide, (i.e., a compound (8.2) wherein X² isBr). For preparing a compound of formula (8.2) wherein X² is I, compound(21.0) is treated with I₂ in a suitable solvent, such as benzene, at atemperature of 30° to 100° C., preferably at 50° to 70° C., to form theiodide, (i.e., a compound (8.2) wherein X² is I).

In Step D, the amine (8.2) is hydrolyzed via substantially the sameprocess as described above for compounds (8.0) and (7.0), to give anamine of the formula (2.5).

Compounds of the formula (6.0) can be prepared from ketones of theformula (14.0) by the process shown in Reaction Scheme 8. ##STR54##

In the process of Reaction Scheme 8, the ketone (14.0) is reduced usinga hydride reducing agent, preferably LiAlH₄, NaBH₄, LiBH₄ or NaCNBH₃, ina suitable solvent, such as THF, Et₂ O, or a C₁ -C₄ alcohol, at atemperature of -80° to 80° C., preferably at -40° to 60° C., with thetemperature and solvent used being selected in accordance with theparticular reducing agent employed, to form the alcohol (22.0). Ingeneral, boron hydrides, such as NaBH₄ and NaCNBH₃, are used inconjunction with alcohol solvents at a temperature of 0° to 50° C.,while the more reactive aluminum hydrides, such as LiAlH₄, are used insolvents such as THF or Et₂ O at a temperature of -40° to 60° C.

The alcohol (22.0) is converted to a compound of formula (6.0). Forpreparing compounds of formula (6.0) wherein L is halo, the alcohol(22.0) is reacted with a halogenating agent, such as PCl₃, PCl₅, POCl₃,SOCl₂, SOBr₂, I₂, PBr₃, PBr₅, or a combination of Ph₃ P and either I₂ orBr₂. For preparing compounds of formula (6.0) wherein L is a group ofthe formula --OC(O)--R⁴⁰ or --OS(O)₂ R²², the alcohol (22.0) is reactedwith an acid chloride of the formula R⁴⁰ C(O)Cl or an anhydride of theformula R⁴⁰ C(O)OC(O)R⁴⁰, or a sulfonyl chloride of the formula R²²S(O)₂ Cl, respectively, in the presence of a base, preferably a tertiaryamine base.

Compounds of the formula (5.0) can be prepared via substantially thesame methods described in PCT International Publication WO95/00497.

Reaction Scheme 12 describes the synthesis of 2-substituted piperazineswherein R² is H, alkyl, alkenyl, or alkynyl, as well as the synthesis of2-substituted piperazines wherein R² is alkyl, alkenyl, or alkynyl whichare substituted with substituent groups 1), 2), 3), 5), 6) and 4),wherein t=0, as defined above, with the exception that R⁶ and R⁷ can notbe a group that is substituted with --C(O)R¹⁴ or --SO₂ R¹⁴. ##STR55##

In Scheme 12, the starting BOC-protected amino acids (32.0) areavailable commercially or can be made by procedures well known in theart. The amino acids (32.0) can be coupled to N-benzylglycine ethylester using a coupling agent such as DCC or DEC in a suitable solvent(e.g., DMF, CHCl₃ or CH₂ Cl₂) to produce a compound of Formula (33.0).Generally, this reaction is conducted at 0° to 35° C., preferably atabout 25° C.

The BOC protecting group of compound (33.0) is hydrolyzed via standardmethods, such as treatment with an acid, preferably TFA or HCl, in asuitable solvent such as CHCl₃ or dioxane at 0° to 50° C., preferably atabout 25° C. and the deprotected dipeptide is cyclized by treatment withbase to produce the compound of formula (34.0).

Compound (34.0) is reduced using a hydride reducing agent, preferablyLiAlH₄ in refluxing Et₂ O or THF to give a piperazine of formula (35.0).The piperazine (35.0) is protected with a BOC group by procedures wellknown in the art to give the compound of Formula (36.0).

The N-benzyl group of compound (36.0) is removed by catalytichydrogenation (e.g., using Pd/C and hydrogen gas under pressure of 1 to100 psi, preferably at about 60 psi, to give the compound of Formula(5.0).

Compounds of Formula 5.0, wherein R² represents alkyl, alkenyl oralkynyl substituted with substituent groups 1), 3), 5) or 4), whereint=0, wherein R⁶ or R⁷ are substituted with --C(O)R¹⁴ or --S(O)₂ R¹⁴ aremade according to the process shown in Reaction Scheme 13. Compounds ofFormula 5.0, wherein R² represents --C(O)NR⁶ R⁷ or --C(O)OR⁶, or whereinR² represents alkyl, alkenyl or alkynyl substituted with a group 6), 7),8), 9), 10), 11), 12), 13) or 4), where t=1 or 2, as defined above, arealso made according to the process of Scheme 2. ##STR56##

In Reaction Scheme 13, the starting amino acids of formula (37.0),wherein R²⁷ is an alkyl, alkenyl or alkynyl group substituted by an --OHgroup or a --COOH group (or its corresponding ester) are availablecommercially or can be made by procedures known in the art. Compound(37.0) is reacted according to the procedures described for the firstfour steps of Reaction Scheme 12 to produce a compound of Formula (40.0)wherein R²⁸ is a hydroxy substituted alkyl, alkenyl or alkynyl group.

Compound (40.0) is then protected with a BOC group and then debenzylatedaccording to the procedures described for steps 5 and 6 of ReactionScheme 12 to produce a compound of Formula (5.10), i.e., a compound offormula (5.0) wherein R² is a hydroxy substituted alkyl, alkenyl oralkynyl group.

A compound of the formula (5.10) where R²⁸ is --CH₂ OH can be oxidizedto produce the corresponding carboxyl group, i.e., where R² is --COOH.This carboxyl group can then be esterified to produce compounds whereinR² is --C(O)OR⁶, or converted to an amide to produce compounds whereinR² is --C(O)NR⁶ R⁷ by procedures well known in the art.

The hydroxy group of R²⁸ of a compound of formula (5.10) can beconverted to a leaving group, such as chloro, mesyloxy or tosyloxy, bytechniques well known in the art. The leaving group can then bedisplaced by various nucleophiles, to produce other compounds of formula(5.0) For example, reaction with: an organometallic reagent to produce acompound where R² is substituted by a substituent 1); a thiol to producea compound where R² is substituted by 4) where t=0; a sulfenyl reagentto produce a compound where R² is substituted by 4) where t=1; asulfinyl reagent to produce a compound where R² is substituted by 4)where t=2, or by a substituent 10); an amine to produce a compound whereR² is substituted by 5); or an alcohol to produce a compound where R² issubstituted by 3). The hydroxy group on R²⁸ of compound (5.10) can alsobe: acylated, e.g. with a suitable chloroformate compound, to produce acompound (5.0) wherein R² is substituted by 8) or 9), respectively; oralkylated to produce a compound (5.0) wherein R² with is substituted by3). When R²⁸ is alkyl having more than one carbon atom, or alkenyl oralkynyl, the hydroxy group can be oxidized, as discussed above, toproduce the corresponding carboxyl group (i.e., substituent 13) whereinR⁶ is H. This carboxyl group can be esterified to produce compoundswherein substituent 13) is --C(O)OR⁶ wherein R⁶ is other than H, orconverted to amides to produce R² with a 12) substituent, by procedureswell known in the art. When the leaving group is displaced by an amine(e.g., HNR⁶ R⁷) to produce a substituent 5) as described above, forthose substituents wherein at least one of R⁶ or R⁷ is H, the resultingamine substituent 5) can subsequently be converted to R² substituted by6), 7) or 11) by reacting, with an acyl halide, a carbamyl halide or asulfonyl halide, respectively, by procedures well known in the art.

Compounds of the formula (5.1), (i.e., racemates of compounds of theformula (5.0) wherein R² is --C(O)NR⁶ R⁷), can be prepared from2-piperazinecarboxylic acid via the process shown in Reaction Scheme 9.##STR57##

In the process of Reaction Scheme 9, 2-piperazine carboxylic acid istreated with FMOC-Cl in the presence of a hydroxide base, preferablyNaOH or KOH, in a suitable solvent, such as a mixture of dioxane andwater, then with BOC-ON under substantially the same conditions to formthe differentially protected compound (23.0).

Compound (23.0) is reacted with an amine of the formula R⁶ R⁷ NH,wherein R⁶ and R⁷ are as defined above, in the presence of DEC or DCC ina suitable solvent, such as DMF or CH₂ Cl₂.

Compound (24.0) is selectively deprotected by treating with TBAF orpiperidine in a suitable solvent, such as DMF, to form a compound of theformula (5.1).

Compounds of the formula (5.2), wherein E is --OR⁶ or --NR⁶ R⁷, (i.e.,racemates of compounds of the formula (5.0) wherein R² is a methyl groupsubstituted by a group of the formula --C(O)OR⁶ or --C(O)NR⁶ R⁷), can beprepared via the process shown in Reaction Scheme 10. ##STR58##

In the process of Reaction Scheme 10, N,N'-dibenzylethylenediamine isreacted with methyl 4-bromocrotonate and a tertiary amine base, such asEt₃ N, in a suitable solvent, such as toluene, to form theN,N'-dibenzylpiperazine derivative (25.0).

Compound (25.0) is hydrogenated over a catalyst, such as Pd/C, to formpiperazine derivative (26.0). The 4-amino group of compound (26.0) isthen protected with a suitable amine protecting group, such as a BOCgroup to form compound (27.0).

Compound (27.0) is hydrolyzed using a hydroxide base, such as NaOH orKOH, and the free amino group is protected as the FMOC derivative usingFMOC-Cl to form compound (28.0).

Compound (28.0) is reacted with an amine of the formula R⁶ R⁷ NH using acoupling agent, such as DEC, in a suitable solvent, such as CH₂ Cl₂ orDMF, then deprotected using TBAF in DMF to form a compound of theformula (5.2), wherein E is --NR⁶ R⁷. Alternatively, compound (28.0) isesterified by reacting with cyanuric fluoride in the presence of atertiary amine base to form an acid fluoride which is reacted with analcohol of the formula R⁶ OH, then deprotected by treating with TBAF orpiperidine in DMF to form a compound of the formula (5.2) wherein E is--OR⁶.

Halide compounds of the formula (13.0) can be prepared as the racemates(13.1), wherein X¹ and R² are as defined above, except for compoundswhere R² is alkyl, alkenyl or alkynyl substituted by a substituentselected from 6), 7), 8), 9), 10), 11), 12), 13) or 4), wherein t=1 or2!, via the process shown in Reaction Scheme 11. ##STR59##

In the process of Reaction Scheme 11, 4-methoxypyridine is reacted witha Grignard reagent of the formula R² MgX¹, wherein R² and X¹ are asdefined above, or alternatively with an organolithium compound of theformula R² Li, wherein R² is as defined above, and with a chloroformateof the formula R²⁵ OC(O)Cl, wherein R²⁵ is phenyl or benzyl, to form acompound of the formula (29.0), wherein R² and R²⁵ are as defined above.The reactions are carried out via substantially the same procedures asdescribed in Comins, et al., Tet. Lett., 27, (38) 4549-4552 (1986).

Compound (29.0) is converted to a compound of the formula (30.0). Forcompounds of the formula (29.0) wherein R²⁵ is benzyl, thistransformation comprises hydrogenation of compound (29.0) using asuitable catalyst, such as Pd/C, followed by N-methylation using asuitable methylating agent, such as methyl iodide, in the presence of abase, such as NaH, to form the compound (30.0). Compounds of the formula(29.0) wherein R²⁵ is phenyl, are converted by hydrolysis of thephenylcarbamate using either aqueous acid or base to form the freeamine, which is methylated, e.g. using methyl iodide and NaH, thenreduced, e.g. by hydrogenation using a suitable catalyst, such as Pd/C,to form the compound (30.0).

Compound (30.0) is reduced using a hydride reducing agent, such as NaBH₄or NaCNBH₃, to form the alcohol (31.0). The alcohol (31.0) is thenconverted to the halide (13.1) by treating with a halogenating agent,such as PCl₃, PCl₅, POCl₃, SOCl₂, SOBr₂, I₂, PBr₃, PBr₅, or acombination of Ph₃ P and either I₂ or Br₂.

Optically active compounds of the formula (13.0) can be prepared viasubstantially the same process as described above for compounds of theformula (13.1) by carrying out a resolution step at a suitableintermediate in the process. For example, resolution of a compound ofthe formula (30.0) using an suitable resolving agent, such as a chiralacid, would give compounds of the formula (31.1) and (31.2), wherein R²is as defined above. The compound (31.1) could then be carried throughthe remaining steps of Reaction Scheme 11 to form a compound of theformula (13.0). ##STR60##

Compounds of the formula (17.0) and (19.0) are known in the art or canreadily be prepared by standard methods.

An alternative method for preparing compounds of the formula (1.1),i.e., compounds of formula (1.0) wherein X is N, is shown in ReactionReaction Scheme 14. ##STR61##

In Reaction Scheme 14, a compound of the formula (6.0) is reacted with acompound of formula (42.0), wherein R¹ and R² are as defined above forcompound (1.0), in a suitable solvent, such as THF, in the presence of abase, such as a tertiary amine base or DBU, with DBU being preferred, toform a compound of formula (1.1).

Compounds of formula (42.0) are prepared as shown in Reaction Scheme 15.##STR62##

In Reaction Scheme 15, compound (45.0), wherein R² is as defined abovefor compound (1.0), the FMOC protecting group is selectivelydeprotected, e.g. by reacting with TBAF or piperidine in a suitablesolvent, such as DMF, to form a compound of formula (44.0), which isthen converted to a compound of formula (43.0) via substantially thesame methods as described above for conversion of compounds of formula(2.0) into compounds of formula (1.0). Compound (43.0) is thendeprotected, e.g. by reacting with an acid, such as TFA, in a suitablesolvent, such as CH₂ Cl₂, to form a compound of the formula (42.0).

Compounds of the formula (45.0) can be prepared via substantially thesame procedures as described above for preparation of compounds of theformula (24.0), (28.0), by switching the order in which the protectinggroups BOC and FMOC are applied, or by similar procedures as thosedescribed above for preparing compounds of formula (5.0) by addingadditional protection/deprotection steps as necessary.

An encoded combinatorial library of compounds of formula (1.0), whereinX is N and R² has a suitable functional group, can be prepared usingcombinatorial methods on a solid phase as described in WO 94/08051(published Apr. 14, 1994), and can be prepared as described in ReactionScheme 16 below. ##STR63## In Scheme 16, a resin, e.g. (resin)-F, isselected which contains a functional group, (--F), which can couple, orform a covalent bond with a suitable linker (A--L--B). Suitablefunctional (--F) groups include primary and secondary amines, hydroxy,thiol, carboxylic acid, halide and the like. The linker (A--L--B) can beany compound having (a) a complementary functional "A--" group (e.g.amine, hydroxy, thiol, carboxylic acid, halide and the like) which cancouple, or form a covalent bond with (resin)-F; (b) a functional "--B"group (e.g. hydroxy, primary or secondary amine, thiol, carboxylic acidand the like) capable of forming a covalent bond with a suitablefunctional group in R² of a substituted, N-protected piperazine (51.0),such as an amide or carboxylic acid group in R² ; and (c) an organic orinorganic moiety "L" capable of having bound to it functional groups "A"and "B". Representative linkers include, but are not limited to4-(bromomethyl)-3-nitrobenzoic acid and 4-(hydroxymethyl)phenol. Thelinker can be coupled to (resin)-F in a suitable solvent (e.g. DCM ormethanol), optionally in the presence of a catalyst suitable for theparticular coupling reaction.

Reagents and reaction conditions for protecting and deprotectingcompounds is well known, as described, for example, in T. W. Greene andP. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., Wileylnterscience, N.Y. 1991, 473 pages. In addition to having a suitablefunctional group in its R² group, piperazine (51.0) has protectinggroups, P¹ and P² orthogonal to each other and to the linker. Suitableprotecting groups include but are not limited to BOC, FMOC, CBZ,allyloxycarbonyl (ALLOC), benzyl, o-nitrophenyl and the like. Theresin/linker (50.0) can be coupled to N-protected piperazine (51.0) inthe presence of a suitable solvent, optionally in the presence of acatalyst suitable for the particular coupling reaction to give thecoupled piperazine (52.0). The " " in moieties such as R² , F and Lindicate that at least one functional group in that moiety is covalentlybonded to another functional group.

Protecting group P¹ can be removed by treatment with a suitabledeprotecting agent or process, including but not limited to TFA,piperidine, hydrogenolysis, photolysis and the like to give partiallydeprotected piperazine (53.0). Piperazine (53.0) can then be reactedwith compound R¹ Y¹, wherein R¹ is as defined before and Y¹ is asuitable leaving group, in a suitable solvent, optionally in thepresence of a catalyst suitable for the particular reaction, to givepartially protected piperazine (54.0). Compound (54.0) can bedeprotected as described above to give deprotected compound (55.0).Compound (55.0) can be alkylated with compound (56.0), wherein A, B, Wand Z are as defined for formula 1.0, and Y² is a suitable leavinggroup, to give compound (57.0).

Compound (1.1) can be prepared by cleaving the coupling between thelinker and R² using a suitable reagent or process suitable for theparticular bond coupling,.e.g. photolysis, acidolysis, hydrolysis andthe like.

In the above processes, it is sometimes desirable and/or necessary toprotect certain R¹ and R² groups during the reactions. Conventionalprotecting groups are operable as described in Greene, T. W.,"Protective Groups In Organic Synthesis," John Wiley & Sons, New York,1981. For example, see the groups listed in Table 1 on page 60 ofWO95/10516 (published Apr. 20, 1995).

Compounds useful in this invention may be prepared by the methodsdisclosed in WO 95/10516, and by the methods described in the examplesbelow. The following preparative examples should not be construed aslimiting the scope of the disclosure. Alternative mechanistic pathwaysand analogous structures within the scope of the invention may beapparent to those skilled in the art.

PREPARATIVE EXAMPLE 1 ##STR64##

Combine 6 g (15.11 mmol) of the title compound of Preparative Example47B, of WO 95/10516, and benzene, and add 2.3 g (9.06 mmol) of iodine.Heat the mixture at reflux for 3 hours, cool, then dilute with 50 mL ofCH₂ Cl₂. Wash the organic phase with 5% NaHSO₃ (aqueous) (3×80 mL), thenwith 1M NaOH (aqueous) (2×80 mL), and dry over MgSO₄. Concentrate to aresidue chromatograph (silica gel, 30% EtOAc/hexanes), to give 3.2 g(42% yield) of the product iodo compound. MS, MH+=509 ##STR65##

The product of Step A is hydrolyzed via substantially the same procedureas described in Example 358, Step A, of WO 95/10516, to give theiodoamine product in 89% yield.

PREPARATIVE EXAMPLE 2 ##STR66##

The product of Preparative Example 47, Step C, of WO 95/10516, (2.42 g)is hydrolyzed via substantially the same procedure as described inExample 358, Step A, of WO 95/10516, to give 1.39 g (69% yield) of thebromoamine product.

PREPARATIVE EXAMPLE 3 ##STR67##

Combine 82.0 g (0.26 mole) of the product of Preparative Example 1, StepG, of WO 95/10516, and 1 L of toluene, then add 20.06 g (0.53 mole) ofLiAlH₄ and heat the reaction mixture at reflux overnight. Cool themixture to room temperature and add ˜1 L of Et₂ O, followed by dropwiseaddition of saturated Na₂ SO₄ (aqueous) until a precipitate forms.Filter and stir the filtrate over MgSO₄ for 30 minutes, then concentratein vacuo to give the product compound in 83% yield. Mass Spec.: MH⁺ =313

PREPARATIVE EXAMPLE 4 ##STR68##

Combine 24.32 g (74.9 mmol) of the Product from Preparative Example 3,Step A, 500 mL of toluene, 83 mL of Et₃ N and 65.9 mL of ethylchloroformate and heat the mixture at reflux overnight. Cool to 25° C.,pour into 200 mL of water and extract with EtOAc. Dry the extract overMgSO₄, concentrate in vacuo to a residue and chromatograph (silica gel,50% EtOAc/hexane) to give 15 g of the product compound. MS: MH⁺ =385.##STR69## Dissolve 3.2 g (10.51 mmol) of tetra-n-butylammonium nitratein 25 mL of CH₂ Cl₂ and add 2.2 g (10.51 mmol, 1.5 mL) of TFAA. Cool to0° C. and add the mixture (via cannula) to a solution of 3.68 g (9.56mmol) of the product of Step A in 50 mL of CH₂ Cl₂ at 0° C., then stirat 0° C. for 3 hours. Allow the mixture to warm to 25° C. while stirringovernight, then extract with saturated NaHCO₃ (aqueous) and dry overMgSO₄. Concentrate in vacuo to a residue and chromatograph (silica gel,30% EtOAc/hexane) to give 1.2 g of the product compound. MS: MH⁺ =430.##STR70##

Combine 2.0 g (4.7 mmol) of the Product of Step B and 150 mL of 85% EtOH(aqueous), add 2.4 g (42 mmol) of Fe filings and 0.24 g (2.1 mmol) ofCaCl₂, and heat at reflux for 16 hours. Filter the hot mixture through abed of celite®, wash the celite® with hot EtOH. Concentrate the filtratein vacuo to give a 100% yield of the product compound. MS: MH⁺ =400.##STR71##

Combine 2.0 g (5.2 mmol) of the Product of Step C and 20 mL of 48% HBr,cool the mixture to -5° C. Stir the mixture at -5° C. for 15 minutes andslowly add a solution of 1.07 g (15.5 mmol) of NaNO₂ in 10 mL of water.Stir for 45 minutes, then quench with 50% NaOH (aqueous) to pH ˜10.Extract with EtOAc, dry the combined extracts over MgSO₄ and concentratein vacuo to give the product compound. MS: MH⁺ =465 ##STR72##

Hydrolyze 4.0 g of the Product of Step D via substantially the sameprocess as described for Example 358, Step A, of WO 95/10516, to give1.39 g of the product compound. MS: MH⁺ =392

PREPARATIVE EXAMPLE 5 ##STR73##

Combine 14.95 g (39 mmol) of the Product of Preparative Example 34A, ofWO 95/10516, and 150 mL of CH₂ Cl₂, then add 13.07 g (42.9 mmol) of(n-Bu)₄ NNO₃ and cool the mixture to 0° C. Slowly add (dropwise) asolution of 6.09 mL (42.9 mmol) of TFAA in 20 mL of CH₂ Cl₂ over 1.5hours. Keep the mixture at 0° C. overnight, then wash successively withsaturated NaHCO₃ (aqueous), water and brine. Dry the organic solutionover Na₂ SO₄, concentrate in vacuo to a residue and chromatograph theresidue (silica gel, EtOAc/hexane gradient) to give 4.32 g and 1.90 g ofthe two product compounds 5(i) and 5(ii), respectively. MS (5(i)): MH⁺=428.2; MS (5(ii)): MH⁺ =428.3 ##STR74##

The compound 5(ii) from Step A (0.20 g) is hydrolyzed via substantiallythe same procedure as described for Example 358, Step A, of WO 95/10516,to give 0.16 g of the product compound.

Using the starting compound indicated and substantially the sameprocedure as described in Preparative Example 5, Step B, the followingproduct compounds are prepared:

    ______________________________________                                        Starting                        Analytical                                    Compound                                                                              Compound                Data                                          ______________________________________                                        Preparative Example 5, Step A, compound 5(i)                                           ##STR75##              --                                                    Preparative Example 5A                                                Preparative Example 6, Step B, compound 6(i)                                           ##STR76##              MS: MH.sup.+  = 466.9                                 Preparative Example 5C                                                ______________________________________                                    

PREPARATIVE EXAMPLE 6 ##STR77##

Combine 22.0 g (51.4 mmol) of the product 5(i) from Preparation 5, StepA, 150 mL of 85% EtOH (aqueous), 25.85 g (0.463 mole) of Fe powder and2.42 g (21.8 mmol) of CaCl₂, and heat at reflux overnight. Add 12.4 g(0.222 mole) of Fe powder and 1.2 g (10.8 mmol) of CaCl₂ and heat atreflux for 2 hours. Add another 12.4 g (0.222 mole) of Fe powder and 1.2g (10.8 mmol) of CaCl₂ and heat at reflux for 2 hours more. Filter thehot mixture through celite®, wash the celite® with 50 mL of hot EtOH andconcentrate the filtrate in vacuo to a residue. Add 100 mL of anhydrousEtOH, concentrate to a residue and chromatograph the residue (silicagel, MeOH/CH₂ Cl₂ gradient) to give 16.47 g of the product compound.##STR78## Combine 16.47 g (41.4 mmol) of the product compound fromPreparative Example 6, Step A, and 150 mL of 48% HBr (aqueous) and coolto -3° C. Slowly add (dropwise) 18 mL of bromine, then slowly add(dropwise) a solution of 8.55 g (0.124 mole) of NaNO₃ in 85 mL of water.Stir for 45 minutes at -3° to 0° C., then adjust to pH=10 by adding 50%NaOH (aqueous). Extract with EtOAc, wash the extracts with brine and drythe extracts over Na₂ SO₄. Concentrate to a residue and chromatograph(silica gel, EtOAc/hexane gradient) to give 10.6 g and 3.28 g of the twoproduct compounds 6(i) and 6(ii), respectively. MS (6(i)): MH⁺ =461.2;MS (6(ii)): MH⁺ =539

PREPARATIVE EXAMPLE 7 ##STR79##

Combine 1.07 g (3.52 mmol) of tetrabutylammonium nitrate, 4 mL ofanhydrous CH₂ Cl₂ and 0.743 g (3.52 mmol) of TFAA, and add the resultingmixture to a solution of 1.22 g (3.20 mmol) of the title compound ofPreparative Example 37, of WO 95/10516, in 8 mL of anhydrous CH₂ Cl₂ atroom temperature. Stir at room temperature overnight, then wash with 20mL of saturated NaHCO₃ (aqueous) and 20 mL of brine, and dry over MgSO₄.Concentrate in vacuo and chromatograph the resulting residue (silicagel, EtOAc/hexane) to give 0.216 g of the product compound 7(i) and 0.27g of the product compound 7(ii). MS: (7(i)) MH⁺ =426, m.p. (7(i))97.5°-99.2° C. ##STR80##

Reduce the product 7(i) from Step A via essentially the same procedureas described in Preparative Example 47, Step B, of WO 95/10516, to givethe product compound. MS: MH⁺ =396 ##STR81##

React the product from Step B with HBr and Br₂ via essentially the sameprocedure as described in Preparative Example 47, Step C, of WO95/10516, to give the product compound. MS: MH⁺ =459 ##STR82##

Hydrolyze 0.83 g of the product from Step C by combining the productwith anhydrous EtOH and concentrated HCl and stirring at reflux. Coolthe reaction mixture to about 0° C. and basify by adding KOH. Extractwith CH₂ Cl₂, dry the extract over MgSO₄, and concentrate in vacuo togive 0.56 g of the product compound. MS: MH⁺ =387

PREPARATIVE EXAMPLE 8 ##STR83##

Combine 7.3 g (26.4 mmol) of the starting ketone (see J. Med. Chem.,4238 (1992)) and 230 mL of THF and cool to 0° C. Add a solution of 32.2mmol of N-methyl-piperidine-4-magnesium bromide in 26 mL of THF and stirat 0°-5° C. for 4 hours. Add 400 mL of EtOAc, wash with saturated NH₄ Cl(aqueous), and dry over MgSO₄. Concentrate in vacuo to a residue, add˜200 mL of CH₂ Cl₂ and stir for 0.5 hours. Filter to collect theresulting solid and concentrate the filtrate to a volume of ˜100 mL andlet sit at 5° C. for 18 hours. Filter and combine the solids to obtain atotal of 7 g (19.4 mmol) of the product compound. m.p.=153.7°-158° C.;MS: (Cl) MH⁺ =376 ##STR84##

Combine 5 g of the product from Step A and 30 mL of TFA at ambienttemperature and stir for 1 hour. Concentrate in vacuo to a residue,dissolve the residue in CH₂ Cl₂ and wash with a saturated NaHCO₃(aqueous). Concentrate in vacuo to give 4.64 g of the product compound.m.p.=136.7°-138° C.; MS: (FAB) MH⁺ =358.1 ##STR85##

Combine 0.6 g (1.75 mmol) of the product of Step B and 25 mL of toluene,add 0.73 mL (5.27 mmol) of Et₃ N and 1.34 mL (14 mmol) of ClCO₂ Et, andheat to 80° C. for 2 hours. Add 0.7 mL more of ClCO₂ Et, heat for 1 morehour, then cool to 25° C. and concentrate in vacuo to a residue.Dissolve the residue in EtOAc and wash with 1N NaOH (aqueous) followedby brine. Dry over MgSO₄, concentrate in vacuo to a residue andchromatograph (silica gel, 10% EtOAc/hexanes) to give 0.55 g of theproduct compound. MS: (FAB) MH⁺ =416.2 ##STR86##

Dissolve 5 g (12.5 mmol) of the product of Step C in 30% HBr in HOAc andheat at 40° C. for 24 hours, then cautiously add the mixture to cold 25%NaOH (aqueous). Extract with CH₂ Cl₂ (3×100 mL), concentrate theextracts to a residue and chromatograph (silica gel, 5% to 30% MeOH/CH₂Cl₂) to give 2.18 g of the product compound. m.p.=159.5°-160.8° C.; MS:(FAB) MH⁺ =344.1

PREPARATIVE EXAMPLE 9 ##STR87## Combine 16.25 g (40.83 mmol) of theproduct of Preparative Example 47, Step B, of WO 95/10516, and a slurryof 7.14 g (61.11 mmol) of NOBF₄ in 100 mL of CH₂ Cl₂ and stir themixture for 3 hours. Add 100 mL of o-dichlorobenzene and heat for 5hours, distilling the CH₂ Cl₂ from the mixture. Concentrate in vacuo toa residue, add 200 mL of CH₂ Cl₂ and wash with water (2×200 mL). Dryover MgSO₄, concentrate in vacuo to a residue, and chromatograph (silicagel, 20% EtOAc/hexane) to give 4.1 g of product compound 9(i) and 4.01 gof Product compound 9(ii). MS (9(i)): MH⁺ =418, MS (9(ii)): MH⁺ =401##STR88##

Hydrolyze the product 9 (i) from Step A via essentially the same processas described for Example 358, Step A, of WO 95/10516, to give theproduct compound. MS: MH⁺ =346

PREPARATIVE EXAMPLE 10 ##STR89##

Combine 10 g (60.5 mmol) of ethyl 4-pyridylacetate and 120 mL of dry CH₂Cl₂ at -20° C. 10.45 g (60.5 mmol) of MCPBA and stir at -20° C. for 1hour and then at 25° C. for 67 hours. Add an additional 3.48 (20.2mmoles) of MCPBA and stir at 25° C. for 24 hours. Dilute with CH₂ CH₂and wash with saturated NaHCO₃ (aqueous) and then water. Dry over MgSO₄,concentrate in vacuo to a residue, and chromatograph (silica gel,2%-5.5% (10% NH₄ OH in MeOH)/CH₂ Cl₂) to give 8.12 of the productcompound. MS: MH⁺ =182.15 ##STR90##

Combine 3.5 g (19.3 mmol) of the product of Step A, 17.5 mL of EtOH and96.6 mL of 10% NaOH (aqueous) and heat the mixture at 67° C. for 2hours. Add 2N HCl (aqueous) to adjust to pH=2.37 and concentrate invacuo to a residue. Add 200 mL of dry EtOH, filter through celite® andwash the filter cake with dry EtOH (2×50 ml). Concentrate the combinedfiltrates in vacuo to give 2.43 g of the title compound.

PREPARATIVE EXAMPLE 11 ##STR91##

Combine 10 g (65.7 mmol) of 3-methoxycarbonylaminopyridine and 150 mL ofCH₂ Cl₂, cool to 0° C. and slowly add (dropwise) a solution of 13.61 g(78.84 mmol) of MCPBA in 120 mL of CH₂ Cl₂ at 0° C. over a period of 1hour. Stir the mixture at 25° C. for 5 days, then wash with saturatedNaHCO₃ (aqueous), then water and dry over MgSO₄. Concentrate in vacuo toa residue and chromatograph (silica gel, 2%-5% (10% NH₄ OH in MeOH)/CH₂Cl₂) to give the product compound. MS: MH⁺ =169

PREPARATIVE EXAMPLE 12 ##STR92##

Combine 5 g (36.0 mmol) of isonicotinic acid 1-N-oxide and 150 mL ofanhydrous DMF, add 5.5 mL (39.6 mmol) of Et₃ N and stir at 0° C. for 0.5hours. Slowly add (dropwise) 8.5 mL (39.6 mmol) of diphenylphosphorylazide at 0° C. over 10 minutes, stir at 0° C. for 1 hour and then at 25°C. for 24 hours (as generally described in Pavia, et al., Journal ofMedicinal Chemistry, 33, 854-861 (1990). Concentrate in vacuo to aresidue and chromatograph (silica gel, 0.5%-1% MeOH/CH₂ Cl₂) to give 5.9g of the product compound.

Using nicotinic acid 1-N-oxide and substantially the same procedure asdescribed for Preparative Example 12 the following compound wasprepared: ##STR93##

PREPARATIVE EXAMPLE 13 ##STR94##

Hydrogenate 25 g (144 mmol) of 3-pyridylacetic acid hydrochloride for144 hours using the procedure described in Preparative Example 15, of WO95/10516, to give 20 g of the product compound. MS: MH⁺ =144. ##STR95##

React 12 g (83.8 mmol) of the product of Step B for 148 hours using theprocedure described in Preparative Example 13, Step B, of WO 95/10516,to give 17.5 g of the product compound. MS: MH⁺ =244.25

PREPARATIVE EXAMPLE 14 ##STR96##

Combine 25 g (164.4 mmol) of methyl 3-pyridylcarbamate and 163.3 mL of1N HCl (aqueous), stir until all of the solid dissolves, thenhydrogenate over 10% Pd/C at 25° C. at 55 psi for 220 hours. Filter,wash the solids with water and treat the combined filtrates with 150 mLof BioRad AG1×8 ion exchange resin (OH⁻). Filter, wash the resin withwater and concentrate the filtrate to a volume of 100 mL. Add 16.43 mL(197.3 mmol) of 37% formalin and hydrogenate over 10% Pd/C at 25° C. at55 psi for 89 hours. Filter, wash the solids with water and concentratein vacuo to give 24.3 g of the title compound. MS: MH⁺ =173.2

PREPARATIVE EXAMPLE 15 ##STR97##

Cool 50.0 g (20.5 mmol) of 8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta1,2-b!pyridin-11-one to 0° C., slowly add 75 mL (93.69 mmol) of sulfurmonochloride over 20 minutes, then slowly add 25 mL (48.59 mmol) of Br₂over 15 minutes. Heat at 95° C. for 20 hour, add 12.5 mL (24.3 mmol) ofBr₂ and heat for a another 24 hours. Cool the mixture, and slowly add toa mixture of CH₂ Cl₂ and 1N NaOH (aqueous) at 0° C. Wash the organicphase with water, dry over MgSO₄ and concentrate in vacuo to a residue.Chromatograph the residue (silica gel, 500 mL CH₂ Cl₂ then 0.2%-5% (10%NH₄ OH in MeOH)/CH₂ Cl₂), then chromatograph again (silica gel, 3%-8.5%EtOAc/hexane) to give 8.66 g of the product compound. MS: MH⁺ =322

PREPARATIVE EXAMPLE 16 ##STR98##

Dissolve 0.16 g (0.46 mmol) of 4-(8-methyl-5,6-dihydro-11H-benzo5,6!cyclohepta 1,2-b!pyridin-11-ylidine)-1-ethoxycarbonylpiperidine, in2 mL EtOH and add 4 mL of 12N HCl. Heat the solution for 3 hours at 85°C., then cool to 25° C. Adjust to pH=10 with 50% NaOH (aqueous) andextract several times with 50 mL of EtOAc. Combine the organic layers,dry them over MgSO₄, and concentrate in vacuo to give the productcompound.

PREPARATIVE EXAMPLE 17 ##STR99##

4-Methoxypyridine is reacted with n-butyl Grignard andphenylchloroformate via substantially the same procedure as described inComins, et al., Tet. Lett., 27, (38) 4549-4552 (1986), to form thedesired unsaturated ketopiperidine product. ##STR100##

The product of Step A is hydrolyzed via substantially the same procedureas described in Preparative Example 34C, of WO 95/10516, to give theamine product. ##STR101##

The product of step B is methylated by reacting with methyl iodide andNaH at room temperature to form the N-methyl product. ##STR102##

The product of Step C is hydrogenated using 10% Pd/C to form the productcompound. ##STR103##

The product of Step D is reacted with NaBH₄ in EtOH at room temperatureto form the alcohol product. ##STR104##

The product of Step E is treated with an excess SOCl₂ in pyridine togive the 4-chloropiperidine.

Following substantially the same procedure as described in PreparativeExample 17, Steps A-F, and using the appropriate Grignard reagent inplace of n-butyl Grignard, the following compounds can also be prepared:

    ______________________________________                                         ##STR105##                                                                   Preparative Example No.                                                                       R.sup.26                                                      ______________________________________                                        18              C.sub.6 H.sub.5 CH.sub.2                                      19              CH.sub.3 OCH.sub.2 CH.sub.2                                   20              CH.sub.3 O(CH.sub.2).sub.3                                    21              n-C.sub.3 H.sub.7 OCH.sub.2 CH.sub.2                          22              CH.sub.3 SCH.sub.2 CH.sub.2                                   23                                                                                             ##STR106##                                                   24                                                                                             ##STR107##                                                   25              C.sub.6 H.sub.5 SDO.sub.2 CH.sub.2 CH.sub.2                   26                                                                                             ##STR108##                                                   27              CH.sub.3 CONH(CH.sub.2).sub.4                                 ______________________________________                                    

EXAMPLE 1 ##STR109##

The title compound from Preparative Example 40, of WO 95/10516, (1equivalent) (1.0 g.) in dry methylene chloride (11.85 ml.) was treatedwith trifluoroacetic acid (30.5 equivalents) (5.92 ml.) and the solutionwas stirred at 25° C. or 0.5 h. The mixture was evaporated to drynessand then reevaporated dryness to give the trifluoroacetic acid salt. Thelatter was dissolved in dry DMF (15 ml.) and triethylamine was addeddropwise until the pH reached 6.2. Sodium triacetoxyborohydride (1.81equivalents) (0.98 g.) and crushed, activated 4 Angstrom molecularsieves (1.48 g.) were added and the mixture was stirred under argon at0° C. A solution of 2(R)-N-tert-butoxycarbonylamino-3-triphenylmethyl-propanal (0.91 equivalents)(1.037 g.) in dry DMF (8 ml.) was added dropwise over 40 min. Themixture was allowed to warm to room temperature over a period of 2 h.The mixture was filtered and evaporated to dryness and the residue wastaken up in ethyl acetate and washed with saturated aqueous sodiumbicarbonate. The organic layer was dried over magnesium sulfate,filtered and evaporated to dryness. The residue was chromatographed on asilica gel column using 0.5-4%(10% concentrated ammonium hydroxide inmethanol)-methylene chloride as the eluant to give a diastereomericmixture of isomer A and isomer B. Yield: 0.9073 g., MH⁺ 825.2.

The N-formyl derivative of the starting reactant was also isolated(Yield: 0.4945 g). Use of dichloroethane as the solvent in the abovereaction instead of DMF avoids the formation of the N-formyl derivative.

The mixture of diastereoisomers A and B (0.683 g.) was separated on asilica gel column using 5% acetone in methylene chloride as the eluantto give pure samples of isomer A (89.2 mg.) and isomer B (66.4 mg.)together with an overlapping mixture of both isomers (384.1 mg.).##STR110##

By essentially the same procedure as described in Example 21 Step B, thetitle compound (Isomers A and B) from Step A above (1 equivalent) (1.024g.) was reacted with triethylsilane (0.089 ml.) and trifluoroacetic acid(1.043 ml.) in methylene chloride (10.24 ml.) to give the title compoundas the hydrochloride salt. Yield: 0.5303 g.; MH⁺ 483.0. PMR data (D₂ O):aromatic proton signals at: 7.28, 7.37 (2H), 8.23, 8.68.

EXAMPLE 2 ##STR111##

The title compound from Example 1B (as the free base) is dissolved inMeOH containing iodine and stirred at 25° C. for 30 mins. the solutionis evaporated to dryness and the CH₂ Cl₂ is taken up in CH₂ Cl₂ andwashed in saturated aqueous NaHCO₃ and then brine. The CH₂ Cl₂ layer isdried over MgSO₄ filtered and evaporated to dryness to give the titlecompound. The title compound is purified on a silica gel column using 3%(10% concentrated NH₄ OH in MeOH)-CH₂ Cl₂ to give the title compound.

EXAMPLE 3 ##STR112##

The 11-hydroxy intermediate (1 equivalent) (1 g.) prepared inPreparative Example 40, of WO 95/10516 was reacted as described inPreparative Example 7B, of WO 95/10516, to give the 11-chlorointermediate. The latter was reacted with 1-tert-butoxycarbonyl-2(S)-n-butylpiperazine (1.1equivalents) (1.1314 g.),prepared as described in Example 3C of PCT International PublicationWO95/00497, by essentially the same procedure as described inPreparative Example 7C, of WO 95/10516, to give the title compound.Yield: 1.7862 g.; MH⁺ 550. ##STR113##

The title compound from Step A above (1.6406 g.) in methanol (16.4 ml.)was treated with 10% (v/v) concentrated sulfuric acid in dioxane (41ml.) and the mixture was stirred at 25° C. for 4 h. The solution wasneutralized with BioRad AG1×8 (OH⁻) resin and filtered. The resin waswashed with methanol and methylene chloride and the combined filtrateswere evaporated to dryness. The residue was chromatographed on a silicagel column using 1% (10% concentrated ammonium hydroxide inmethanol)-methylene chloride as the eluant to give the title compound.

Yield: 1.2451 g., MH⁺ 450. ##STR114##

The title compound from step B is reacted as described in Example 1Aabove to give the title compound. The latter is purified on a silica gelcolumn using 0.5%-1% (10% concentrated NH₄ OH in MeOH) --CH₂ Cl₂ to givethe title compound. ##STR115##

The title compound from Step C above is reacted as described in Example1B above to give the title compound as its HCl salt.

EXAMPLES 4-8 ##STR116##

The title compound from Example 13A of WO 95/00497 is reacted withbenzyloxycarbonyl chloride under standard conditions known to oneskilled in the art, to give the N-Cbz protected alcohol shown above.After purification in the usual way the latter may be reacted with avariety of reagents shown in Column 1 of Table 1 to give thecorresponding N-Cbz protected intermediates where R is as defined inColumn 2 of Table 1. After purification in the usual way the latter maybe deprotected using mild catalytic hydrogenation procedures known inthe art, to give after suitable purification, the final desiredintermediates shown in Column 2 of Table 1.

                  TABLE 1                                                         ______________________________________                                        Column 1         Column 2                                                     ______________________________________                                         ##STR117##                                                                                     ##STR118##                                                                   Prepared as described in Example                                              14A or WO 95/00497.                                                           Example 4.                                                   C.sub.6 H.sub.5 SSC.sub.6 H.sub.5 + (n-Bu).sub.3 P                                              ##STR119##                                                                   Prepared as described in Example                                              20B and 20C of WO 95/00497.                                                   Example 5.                                                    ##STR120##                                                                                     ##STR121##                                                   ##STR122##                                                                                     ##STR123##                                                  n-C.sub.3 H.sub.7 I + NaH                                                                      R = n-C.sub.3 H.sub.7 O                                                       Prepared as described in Example                                              13C of WO 95/00497.                                                           Example 8                                                    ______________________________________                                    

EXAMPLE 9 ##STR124##

The title compound from Example 27D of WO 95/00497 is converted by thescheme shown above, using standard procedures known to one skilled inthe art, into 1-BOC-2(S)-(4-acetylaminobutyl)piperazine.

EXAMPLES 10-19

By essentially the same procedures as set forth in Example 3 above butusing the compounds set forth in Column 1, Table 2 (below), in place of1-BOC-2(S)-n-butylpiperazine, one can obtain compounds of the formula:##STR125## wherein R² is as listed in Column 2, Table 2

                                      TABLE 2                                     __________________________________________________________________________    Column 1             Column 2                                                 __________________________________________________________________________     ##STR126##          R.sup.2 = C.sub.6 H.sub.5 CH.sub.2 Example 10            Prepared as described in Example                                              6C of WO 95/00497.                                                             ##STR127##          R.sup.2 = CH.sub.3 OCH.sub.2 CH.sub.2 Example 11         Prepared as described in Example                                              7D of WO 95/00497.                                                             ##STR128##          R.sup.2 = CH.sub.3 SCH.sub.2 CH.sub.2 Example 12         Prepared as described in Example                                              8C of WO 95/00497.                                                             ##STR129##          R.sup.2 = CH.sub.3 O(CH.sub.2).sub.3 Example 13          Prepared as described in                                                      Example 18D of WO 95/00497                                                     ##STR130##                                                                                         ##STR131##                                              Prepared as described in Example                                              4 above                                                                        ##STR132##                                                                                         ##STR133##                                              Prepared as described in Example                                              5 above                                                                        ##STR134##                                                                                         ##STR135##                                              Prepared as described in Example                                              6 above                                                                        ##STR136##                                                                                         ##STR137##                                              Prepared as described in Example                                              7 above                                                                        ##STR138##          R.sup.2 = n-C.sub.3 H.sub.7 O(CH.sub.2).sub.2                                 Example 18                                               Prepared as described in Example                                              8 above                                                                        ##STR139##          R.sup.2 = CH.sub.3 CONH(CH.sub.2).sub.4 Example 19       Prepared as described in Example                                              9 above                                                                       __________________________________________________________________________

EXAMPLE 20 ##STR140##

The title compound from Preparative Example 40, of WO 95/10516, (1equivalent) (1 g), N,N'-bis-BOC-L-cystine (0.45 equivalents) (0.501 g),DEC (0.9 equivalent) (0.4366 g), HOBT (0.9 equivalent) (0.3078 g) andN-methylmorpholine (0.9 equivalent) (0.2304 g) were dissolved inanhydrous DMF (25 mL) and the mixture was stirred at 25° C. under argonfor 68 hours. The mixture was evaporated to dryness and taken up in CH₂Cl₂ and washed with saturated aqueous NaHCO₃ and then water. The CH₂ Cl₂layer was dried over MgSO₄ filtered, and evaporated to dryness. Theresidue was chromatographed on a silica gel column (60×2.5 cm) using0.5%-1% (10% concentrated NH₄ OH in MeOH) --CH₂ Cl₂ to give the titlecompound. Yield: 1.09 g. MH⁺ 1189.7. ##STR141##

The title compound from Step A above (1 equivalent) (0.944 g) was addedto MeOH (10 mL). A 10% (v/v) concentrated H₂ SO₄ in dioxane solution (20mL) was added and the solution was stirred at 25° C. under argon for 2hours. The mixture was neutralized with BioRad AG1×8(OH⁻) resin. Theresin was filtered off and washed with MeOH and CH₂ Cl₂. The combinedfiltrates were evaporated to dryness and the residue was chromatographedon a silica gel column (110×2.5 cm) using 5% (10% concentrated NH₄ OH inMeOH)--CH₂ Cl₂ to give the title compound. Yield: 0.6879 g, MH⁺ 989.

CMR data (δ_(c) (CDCl₃)) for the product of Step B was: (1) tricyclic:(a) CH₂ : 31.3, 31.4, (b) CH: 147.9, 142.1, 133.3, 127.1, 131.4, 79.7,and (c) C: 120.9, 141.7, 135.0, 136.1, 137.6, 156.3; (2) piperazine: (a)CH₂ : 46.2, 52.6, 52.0, 43.0; and (3) Piperazine N-substituent: (a) CH₂: 45.0, (b) CH: 51.0, and C: 172.2. ##STR142##

The title compound from Step B above is dissolved in a mixture ofanhydrous MeOH and THF and NaBH₄ is added the mixture is stirred underargon at 25° C. for 2 hours. The solution is evaporated to dryness andthe residue is taken up in CH₂ Cl₂ and washed with water. The CH₂ Cl₂layer is dried over MgSO₄, filtered and evaporated to dryness to give aresidue which is purified by substantially the same procedure asdescribed for Example 1E of WO95/00497 to give the title compound as itsHCl salt.

Alternatively, zinc dust and 1.0N HCl may be used in place of NaBH₄ toeffect the above reduction.

EXAMPLE 21 ##STR143##

The title compound from Preparative Example 40, of WO 95/10516, (1equivalent) (1 g), N-BOC-S-trityl-L-cysteine (1.34 equivalents) (1.584g) DEC (1.34 equivalents) (1.5 g), HOBT (1.34 equivalents) (0.4618 g),and N-methylmorpholine (1.34 equivalents) (0.1048 g) (0.114 mL) weredissolved in anhydrous DMF (25 mL) and the mixture was stirred underargon at 25° C. for 68 hours. The solution was evaporated to dryness andthe residue was taken up in CH₂ Cl₂ and washed with saturated aqueousNaHCO₃ and then water. The CH₂ Cl₂ layer was dried over MgSO₄, filteredand evaporated to dryness and the residue was chromatographed on asilica gel column (60×2.5 cm) using 0.5% (10% concentrated NH₄ OH inMeOH)--CH₂ Cl₂ to give the title compound. Yield: 2.04 g, MH⁺ 837.6.##STR144##

The title compound from Step A above (1 equivalent) (0.5 g.) wasdissolved in dry methylene chloride (5 ml.) and triethylsilane (4.07equivalents) (282.1 mg.) (0.388 ml.) was added under an argonatmosphere. Trifluoroacetic acid (2.5 ml.) was added and the solutionwas stirred at 25° C. for 1 h. The solution was evaporated to drynessand the residue was partitioned between water and hexane. The aqueouslayer was separated and passed over BioRad AG3×4(Cl⁻) resin (100 ml.)and the resin was washed with water. The combined eluates and wash werelyophilized to give the title compound as the hydrochloride salt. Yield:306.9 mg., MH⁺ 497.2. The method described above is essentially the sameas described for Example 1E of WO95/00497. H¹ NMR (D₂ O): Aromaticproton signals at: 7.00 (2H), 7.17, 7.50, 8.21. ##STR145##

The title compound from Step A above (1 equivalent) (30 mg) wasdissolved in dry CH₂ Cl₂ (1 mL) and triethylsilane (4 equivalents)(16.93 mg) (0.0233 mL) was added followed by TFA (1 ml). The mixture wasstirred at 25° C. under argon for 1 hour and then neutralized withBioRad AG1×8 (OH⁻) resin. The resin was filtered off and washed withMeOH and CH₂ Cl₂. The combined filtrates were evaporated to dryness togive the title compound. ##STR146##

The title compound from Step B above is reduced as described in Example20 Step C above to give the title compound. ##STR147##

The title compound from step A above (1 equivalent) (1.2 g.) was addedto methanol (10 ml.) and a solution of 10% concentrated sulfuric acid indioxane (v/v) (30 ml.) was added. The mixture was stirred at 25° C.under argon for 2 h. The mixture was diluted with methylene chloride andmethanol and neutralized with BioRad AG1×8 (OH⁻) resin. The resin wasfiltered off and washed with methanol followed by methylene chloride.The combined filtrates were evaporated to dryness to give a solidresidue that was chromatographed on a silica gel column using 2% (10%concentrated ammonium hydroxide in methanol)-methylene chloride as theeluant to give the title compound. Yield: 1.0 g., MH⁺ 739.2.

EXAMPLE 22 ##STR148##

The title compound from Preparative Example 3E, of WO 95/10516, isreacted under the same conditions described in Example 1A above to givethe title compound, which is purified in the usual way. ##STR149##

The title compound from Step A above is deprotected under similarconditions to those described in Example 1B above to give the titlecompound.

EXAMPLE 24 ##STR150##

The title compound from Preparative Example 20A, of WO 95/10516, isreacted with a substituted Grignard reagent from Example 23 above underessentially the same conditions as described in Preparative Examples 2Dand 2E, of WO 95/10516, to give the title compound. ##STR151##

The title compound from Step A above is reacted under essentially thesame conditions as described in Preparative Examples 1F and 1G, of WO95/10516, to give the title compound. ##STR152##

The title compound from Step B above is reacted as described in Example1A above to afford the title compound. ##STR153##

The title compound from Step C above is reacted as described in Example1B above to give the title compound.

EXAMPLE 25 ##STR154##

The title compound from Example 24B above is reacted with CF₃ SO₃ H asdescribed in Preparative Example 34A, of WO 95/10516, to afford thetitle compound. ##STR155##

The title compound from Step A above is reacted as described in Example1A above to give the title compound. ##STR156##

The title compound from Step B above is reacted as described in Example1B above to give the title compound.

EXAMPLE 26 ##STR157##

The title compound from Example 24B above is reacted with either LiAlH₄in refluxing toluene, or preferably with DIBAL-H in refluxing toluene togive the title compound. ##STR158##

The title compound from Step A above is reacted as described in Example1A above to give the title compound. ##STR159##

The title compound from Step B above is reacted as described in Example1B above to afford the title compound.

EXAMPLE 27 ##STR160##

The title compound from Example 3B above is reacted with2-S-trityl-3-N-BOC-iso-cysteine under essentially the same conditions asdescribed in Example 21A above to give the title compound. The protectediso-cysteine is prepared by methods known to one skilled in the art fromiso-cysteine (Gustavson, et al., Syn. Comm., 21, (2) 265-270 (1991)).##STR161##

The title compound from Step A above is reacted as described in Example1B above to give the title compound.

EXAMPLE 28 ##STR162##

The title compound from Preparative Example 4 of WO89/10369 is convertedinto the title compound by methods similar to those described inWO89/10369. ##STR163##

The title compound from Step A above is reacted with the substitutedpiperidine from Example 4 above under similar conditions to thosedescribed in WO89/10369 to give the title compound. ##STR164##

The title compound from Step B above is reacted as described in Example3B above to give the title compound. ##STR165##

The title compound from Step C above is reacted as described in Example1A above to give the title compound. ##STR166##

The title compound from Step D above is reacted as described in Example1B above to give the title compound.

EXAMPLE 29 ##STR167##

The title compound from Example 3B above is reacted with the acid,##STR168## (prepared as described in U.S. Pat. No. 4,470,972 and E. M.Smith, et al., J. Med. Chem., 32, 1600 (1989)), under similar conditionsto those described in Example 20A to give the title compound. ##STR169##

The title compound from Step A above is reacted with base to afford thetitle compound.

EXAMPLE 30 ##STR170##

Combine 0.5 g of the product of Preparative Example 1, Step G, of WO95/10516, 0.54 g of N-BOC-S-(p-methoxybenzyl)-L-cysteine, 0.321 g ofDEC, 0.226 g of HOBT, 0.176 g of N-methylmorpholine and 15 mL of DMF at0° C., then stir the mixture for 3 days at room temperature. Concentratein vacuo to a residue which is dissolved in CH₂ Cl₂ and washedsuccessively with saturated NaHCO₃ (aqueous) and brine. Dry the organicsolution over Na₂ SO₄ and concentrate in vacuo to a residue.Chromatographed (silica gel, 98% CH₂ Cl₂ /MeOH+NH₄ OH) to give theproduct compound. MS: MH⁺ =634.

EXAMPLE 31 ##STR171##

Combine 0.1 g of the product of Example 30, 4 mL of THF and 2 mL of 4NHCl in dioxane and stir the mixture for overnight at room temperature.Concentrate in vacuo to give 0.06 g of the product compound. MS: MH⁺=534.

EXAMPLE 32 ##STR172##

Dissolve 5.25 g (25.85 mmol) of 2-piperazine carboxylic acid.2HCl in 160mL of 1:1 dioxane/H₂ O, and adjust the pH to 11 with 50% NaOH (aq.).Slowly add (in portions) a solution of 7.21 g (29.28 mmol) of BOC-ON in40 mL of 1:1 dioxane/H₂ O while maintaining the pH at 11 with 50% NaOH(aq.) during the addition. Stir at room temperature for 5 hours, thencool to 0° C. and adjust to pH 9.5 with 50% NaOH(aq.). Slowly add (inportions) a solution of 7.34 g (28.37 mmol) of FMOC-Cl in 40 mL ofdioxane, maintaining a pH of 9.5 during the addition with 50% NaOH(aq.). Warm the mixture to room temperature and stir for 20 hours. Washwith Et₂ O (3×150 mL), adjust to pH=2-3 with 6N HCl (aq), and extractwith toluene (3×150 mL). Dry the combined extracts over Na₂ SO₄ andconcentrate in vacuo to a volume of 150 mL. Chill at -20° C. overnight,filter to collect the resulting solids, wash with hexane and dry thesolids in vacuo to give 5.4 g of the product compound. ##STR173##

Slowly add 2.0 g (9.26 mmol) of 2-nitrobenzylbromide to 37 mL of a 2Msolution of CH₃ NH₂ in THF, then stir at room temperature for 16 hours.Dilute with 200 mL of EtOAc, wash with water (3×60 mL), then dry theorganic phase over Na₂ SO₄ and concentrate in vacuo to give 1.53 g ofthe product compound. ##STR174##

Combine 2.74 g (6.05 mmol) of the product of Step A, 4.22 mL of Hunigsbase, 2.76 g (7.26 mmol) of HATU, and a solution of 1.00 g (6.05 mmol)of the Product of Step B in 25 mL of CH₂ Cl₂, and stir at roomtemperature for 16 hours. Dilute with 75 mL of EtOAc wash successivelywith 10% HCl (aqueous) (2×40 mL), saturated NaHCO₃ (aqueous) (2×40 mL)and 40 mL of brine. Dry the organic phase over MgSO₄ concentrate invacuo to a residue and chromatograph (silica gel, 2% MeOH/CH₂ Cl₂) togive 2.71 g of the product compound. ##STR175##

Combine 1.00 g (1.67 mmol) of the Product of Step C, 8 mL of DMF and0.18 mL (1.83 mmol) of piperidine, and stir at room temperature for 4hours. Concentrate in vacuo to a residue and chromatograph (silica gel,4% MeOH/CH₂ Cl₂) to give 0.34 g of the product compound. ##STR176##

Combine 0.30 g (0.789 mmol) of the Product of Step D and 8 mL of CH₂Cl₂, then add 0.164 g (0.947 mmol) of 3-pyridylacetic acid.HCl, 0.116 g(0.947 mmol) of DMAP and 0.195 g (0.947 mmol) of DCC, and stir at roomtemperature for 16 hours. Chromatograph (silica gel, 4% MeOH/CH₂ Cl₂) togive 0.37 g of the Product compound. ##STR177##

Add 0.5 mL of TFA to a solution of 0.25 g (0.502 mmol) of the Product ofStep E in 5 mL of CH₂ Cl₂, and stir at room temperature for 4 hours.Concentrate in vacuo to a residue, add 60 mL of EtOAc and washsuccessively with saturated K₂ CO₃ (aqueous) (2×20 mL) and 30 mL ofbrine. Dry the organic phase over Na₂ SO₄ and concentrate in vacuo togive 0.170 g of the Product compound. ##STR178##

Combine 0.096 g (0.242 mmol) of the product of Step F, 0.083 g (0.242mmol) of the chloride Product of Preparative Example 40, Step B, of WO95/10516, and 1 mL of THF, then 0.037 g (0.242 mmol) of DBU, and heat at60° C. for 6 hours. Concentrate in vacuo to a residue and chromatograph(silica gel, 2% to 5% MeOH/CH₂ Cl₂) to give 0.035 g of the titlecompound (Example 32) along with 0.042 g of a product of formula:##STR179##

Analytical data for Example 32¹ : H NMR (CDCl₃): 2.01-3.08 (m, 9H);3.55-3.86 (m, 4H); 3.90-4.10 (m, 2H); 4.21-4.38 (m, 2H); 5.23-5.39 (m,2H); 7.09-7.31 (m, 5H); 7.44 (t, 1H); 7.527.70 (m, 3H); 8.09 (br. d,1H); 8.37-8.52 (m, 3H).

Analytical data for Example 32-A: ¹ H NMR (CDCl₃): 1.85-2.21 (m, 3H);2.44-2.86 (m, 5H); 3.01-3.46 (m, 3H); 3.52-4.50 (m, 5H); 5.01 (br. s,1H); 5.48-5.68 (m, 1H); 7.07-7.99 (m, 3H); 7.24-7.31 (br. s, 1H);7.55-7.65 (m, 2H); 8.32-8.57 (m, 3H).

Using substantially the same procedure as described for Example 32,Steps A-G, but substituting the indicated amine for CH₃ NH₂ in Step B,and or the indicated acid for 3-pyridylacetic acid in Step E, thefollowing compounds were also prepared:

    __________________________________________________________________________    Reagents used in Step B and/or                                                Step E         Compound                                                       __________________________________________________________________________    Step B: i-propyl-amine                                                                        ##STR180##                                                                   Example 32-B                                                   Step B: i-propyl-amine Step E: 4-pyridyl-acetic acid                                          ##STR181##                                                                   Example 32-C                                                   __________________________________________________________________________

Analytical data for Example 32-B: ¹ H NMR (CDCl₃): 0.9-1.07 (m, 6H);1.80-2.23 (m, 2H); 2.36-2.89 (m, 3H); 2.97-3.38 (m, 2H); 3.47-4.10 (m,5H); 4.08-4.18 (m, 1H); 4.41 (br. d, 1H one diastereoisomer); 4.90 (br.s, 1H one diastereoisomer); 5.17-5.25 and 5.60-5.65 (m, 2H); 7.00-7.13(m, 3H); 7.16-7.23 (br. s, 1H); 7.50-7.60 (m, 2H); 8.27-8.49 (m, 3H).

Analytical data for Example 32-C: ¹ H NMR (CDCl₃): 0.98-1.11 (m, 6H);1.82-2.21 (m, 2H); 2.40-2.82 (m, 3H); 3.10 (t, 1H); 3.17-3.40 (m, 1H);3.50-3.62 (m, 1 H); 3.70-4.32 (m, 5H); 4.49 (br. d, 1H onediastereoisomer); 4.98 (br. s, 1H one diastereoisomer); 5.20-5.36 and5.61-5.69 (m, 2H); 7.05-7.20 (m, 5H); 7.54-7.62 (m, 1H); 8.32-8.38 (m,1H); 8.52-8.59 (m, 2H).

EXAMPLE 33 ##STR182##

Combine 12.05 g (48.5 mmol) of ethyl 1-N-benzyl-2-piperazinecarboxylatein 100 mL of THF with 10.59 g (48.5 mmol) of di-t-butyldicarbonate andstir at room temperature for 3 hours. Concentrate in vacuo to give 17.17g of the product compound. ##STR183##

Combine 17.17 g of the product compound from Step A, 150 mL of MeOH, 7.5mL of HOAc and 3.4 g of 10% Pd/C, and hydrogenate with H₂ (50 psi) for18 hours at room temperature. Filter through celite®, wash the filtercake with MeOH and concentrate the filtrates in vacuo to a residue.Dissolve the residue in 300 mL of EtOAc and wash successively withsaturated Na₂ CO₃ (aqueous) (2×150 mL) and 100 mL of brine. Dry overMgSO₄ and concentrate in vacuo to give 11.54 g of the product compound.##STR184##

Combine 0.26 g (1 mmol) of the product compound from Step B, 1 mL of CH₂Cl₂, 0.174 g (1 mmol) of 3-pyridylacetic acid, 0.147 g (1.2 mmol) ofDMAP and 0.248 g (1.2 mmol) of DCC, and stir at room temperature for 40hours. Concentrate in vacuo to a residue and chromatograph (silica gel,5% MeOH/CH₂ Cl₂) to give 0.315 g of the product compound. ##STR185##

Combine 0.196 g (0.521 mmol) of the product compound from Step C and 0.5mL of TFA, and stir at room temperature for 40 hours. Concentrate invacuo to a residue, add 50 mL of EtOAc and wash with 10 mL of 1N Na₂ CO₃(aqueous). Dry over Na₂ SO₄ and concentrate in vacuo to give 0.077 g ofthe product compound. ##STR186##

Combine 0.075 g (0.272 mmol) of the product compound from Step D, 0.091g (0.265 mmol) of the chloride Product of Preparative Example 40, StepB, of WO 95/10516, 2 mL of THF and 0.40 g (0.265 mmol) of DBU, and stirat 50° C. for 24 hours. Cool to 25° C., concentrate in vacuo to aresidue, and chromatograph (silica gel, 5% MeOH/CH₂ Cl₂) to give 0.034 gof the product compound. ¹ H NMR (CDCl₃): 1.12 and 1.14 (t, 3H);1.55-1.82 (m, 1H); 1,92-2,50 2H); 2.53-2.81 (m, 2H); 3.03-3.25 (m, 1H);3.28-3.45 (m, 1H); 3.53-3.71 (m, 2H); 3.74 (s, 2H); 3.85-4.19 (m, 3H);4.31 and 4.32 (s, 1H); 5.10-5.1 8 (m,3H).

EXAMPLE 34 ##STR187##

Combine 12 mL (50 mmol) of N,N'-dibenzylethylenediamine, 14 mL (100mmol) of Et₃ N and 250 mL toluene at 0° C., add 7 mL (50 mmol) of methyl4-bromocrotonate (7 mL, 50 mmol), slowly warm to room temperature andstir for 24 hours. Filter, concentrate the filtrate in vacuo to aresidue and treat with 10% aqueous HCl (300 mL). Filter again and washthe filtrate EtOAc (2×100 mL). Basify the filtrate with K₂ CO₃, extractwith EtOAc (3×150 mL), wash the combined extracts with brine, dry overMgSO₄ and concentrate in vacuo to give 13.7 g of the product compound. ¹H NMR (CDCl₃) 2.28-2.50 (m, 4H), 2.5-2.75 (m, 4H), 3.1 (bs, 1H), 3.42(d, 2H), 3.52 (d, 1H), 3.6 (s, 3H), 3.75 (dd 1H), 7.15-7.35 (m, 10H).##STR188##

Combine 13.7 g (40 mmol) of the product of Step A, 150 mL of MeOH, 50 mLof 1N HCl (aqueous) and 3 g of 10% Pd/C and hydrogenate with H₂ (50 psi)for 24 hours. Filter, concentrate the filtrate in vacuo to remove mostof the MeOH, and basify with K₂ CO₃ to pH=9-10. Slowly add 9.8 g (40mmol) of BOC-ON at 0° C. and stir at 0° for 1 hour. Slowly warm up toroom temperature, stir 2 hours, and extract with EtOAc (2×200 mL). Treatthe combined extracts with 50 mL of 10% HCl (aqueous), wash the aqueouslayer with EtOAc, basify with K₂ CO₃ and extract three times with EtOAc.Wash the combined organic layers with brine, dry over MgSO₄ andconcentrate in vacuo to give 7.89 g of the product compound.

¹ H NMR (CDCl₃): 1.4 (s, 9H), 2.31 (dd, 1H), 2.37 (dd, 1H), 2.55 (b,1H), 2.69-3.02 (m. 4H), 3.75 (s, 3H), 3.88 (b, 2H). ##STR189##

Combine 5.2 g (20 mmol) of the product of Step B, 60 mL of THF, 60 mL of1N NaOH (aqueous) and stir at room temperature for 6 hours. Cool to 0°C., add 10% HCl (aqueous) to adjust to pH=9-10, then add 5.2 g (20 mmol)of FMOC-Cl. Stir at room temperature for 6 hours, (adding 1N NaOH(aqueous) to maintain pH=9-10), then acidify with 10% HCl to pH=1.Extract twice, wash the combined organic layers with brine, dry overMgSO₄ and concentrate in vacuo to give 8.56 g of the product compound. ¹H NMR (CDCl₃): 1.4 (s, 9H), 2.5-3.0 (m, 5H), 3.9-4.2 (m, 6H), 4.5(m,1H), 7-25 (t, 4H), 7.32(t, 4H), 7.48(d, 4H), 7.75(d, 4H). ##STR190##

Combine 460 mg (1 mmol) of the product of Step C, 5 mL of CH₂ Cl₂, 230mg (1.2 mmol) of DEC and 130 μL (1.5 mmol) of i-propylamine, and stir at25° C. for 6 hours. Treat with 10 mL of 1N HCl (aqueous), extract with30 mL of EtOAc, wash the extract with saturated NaHCO₃ (aqueous) and dryover Na₂ SO₄. Concentrate in vacuo to give 454.6 mg of the productcompound. ##STR191##

Combine a solution of 150 mg (0.3 mmol) of the product of Step D in DMFwith 142 mg (0.45 mmol) of TBAF, and stir at 25° C. for 0.5 hours. Treatwith 5 mL of 1N HCl (aqueous) and wash with 10 mL of EtOAc. Basify withsaturated K₂ CO₃, extract three times with EtOAc and dry the combinedextracts over MgSO₄. Concentrate in vacuo to a residue. Treat theresidue with 3-pyridylacetic acid via substantially the same procedureas described for Example 33, Step C, to give 106.2 mg of the productcompound. ##STR192##

Combine 40 mg (0.1 mmol) of the product of Step E, 2 mL of CH₂ Cl₂ and 1mL of TFA, and stir at 25° C. for 0.5 hours. Concentrate in vacuo to aresidue. Combine the residue with 90 μL (0.6 mmol) of DBU in 2 mL ofTHF, add 40 mg (0.12 mmol) of the product of Preparative Example 40,Step B, of WO 95/10516, and stir at 60° C. for 8 hours. Concentrate invacuo to a residue and chromatograph to give 48.2 mg of the productcompound.

EXAMPLE 36 ##STR193##

The title compound from Example 3B above (1 equivalent) (0.5 g.) wasreacted with the title compound from Preparative Example 10B (1.5equivalents) (0.2559 g.) and DEC (1.5 equivalents) (0.3203 g.), HOBT(1.5 equivalents) (0.169 g.) and N-methylmorpholine (1.5 equivalents)(0.245 ml.) in dry DMF (15 ml.) at 25° C. for 22 h. The reaction wasworked up essentially as described in Example 20A and the product waspurified on a silica gel column using 2.25% (10% concentrated ammoniumhydroxide in methanol)-methylene chloride as the eluant to give thetitle compound.

Yield: 609.4 mg., MH⁺ 585.0.

CMR data (δ_(c) (CDCl₃)) for the title compound: (1) tricyclic: (a) CH₂: 29.7/29.8/29.9/30.0/30.2/30.4, (b) CH: 146.6/146.7, 140.6/140.9,132.1, 129.8/129.9/130.0/130.1, 125.9, 78.3/78.4/78.5, and (c) C: 119.6,140.2/140.4, 134.6, 136.2/136.3, 136.4, 154.6/154.7/154.9/155.0; (2)piperazine: (a) CH₃ : 13.5/13.6, (b) CH₂ : 22.0/22.1, 28.7, 27.6/27.9,37.0/37.1/38.0/38.5, 41.4/41.5, 50.8/51.6, 53.1/53.2/53.5/53.8/53.9, and(c) CH: 49.0; and (3) piperazine N-substituent: (a) CH₂ : 51.2, (b) CH:126.3, 126.3,138.5, 138.5, and (c) C: 133.8, 166.4/166.7.

EXAMPLE 37 ##STR194##

The title compound from Example 3B above (1 equivalent) (0.658 g.) wasreacted with the title compound from Preparative Example 17D, of WO95/10516, (1.3 equivalents) (0.4637 g.) and DEC (1.3 equivalents)(0.3654 g.), HOBT (1.3 equivalents) (0.2575 g.) and N-methylmorpholine(1.3 equivalents) (0.21 ml.) in dry DMF (25 ml.) at 25° C. for 25 h. Theproduct was isolated as described in Example 20A and used directly inStep B below. ##STR195##

The title compound from Step A above was dissolved in methanol (5 ml.)and 10% (v/v) concentrated sulfuric acid in dioxane (15 ml.) was addedand the reaction was run and worked up as described in Example 20B togive the title compound. Yield: 0.312 g., MH⁺ 575.4. ##STR196##

The title compound from Step B above (1 equivalent) (0.310 g.) wasdissolved in dry methylene chloride (5 ml.) and trimethylsilylisocyanate(6 equivalents) (0.3733 g.) (0.439 ml.) was added. The mixture wasstirred at 25° C. for 77 h. under argon. Additionaltrimethylsilylisocyanate (6 equivalents) (0.3733 g.) (0.439 ml.) wasadded and the reaction was allowed to proceed for a total of 106 h. Themixture was diluted with methylene chloride and washed with saturatedaqueous sodium bicarbonate, water and then dried over magnesium sulfate.Filtration followed by evaporation gave the title compound that waspurified on a silica gel column using 2%(10% concentrated ammoniumhydroxide in methanol)-methylene chloride as the eluant to give thetitle compound.

Yield: 0.1758 g., MH⁺ 618.2.

CMR data (δ_(c) (CDCl₃))for the title compound: (1) tricyclic: (a) CH₂ :29.8, 30.1, (b) CH: 146.6/146.7, 140.8/140.9, 132.1, 125.8/125.9,128.9/129.9/130.0/130.1, 78.5/78.6, and (c) C: 119.6, 140.2/140.4,133.7/133.8, 134.7/134.8, 136.2/136.3, 155.0/155.7; (2) piperazine: (a)CH₃ : 13.5/13.6, (b) CH₂ : 40.9/41.0, 51.1/51.4/51.9,53.2/53.3/53.4/-53.9/54.2, 36.5, 22.1/22.2, 27.7/27.8, and (c) CH: 48.4;and (3) piperazine N-substituent: (a) CH₂ : 44.0, 31.5, 31.5, 44.0,39.1, (b) CH: 32.6, and (c) C: 157.5, 169.1/169.4.

EXAMPLE 38 ##STR197##

The title compound from Example 11B above (1 equivalent) (0.4 g.) wasreacted with the title compound from Preparative Example 10B (1.5equivalents) (0.2038 g.) and DEC (1.5 equivalents) (0.2552 g.), HOBT(1.5 equivalents) (0.1346 g.) and N-methylmorpholine (1.5 equivalents)(0.195 ml.) in dry DMF (15 ml.) at 25° C. for 17 h. The reaction wasworked up essentially as described in Example 20A and the product waspurified on a silica gel column using 3% (10% concentrated ammoniumhydroxide in methanol)-methylene chloride as the eluant to give thetitle compound.

Yield: 539.6 mg., MH⁺ 587.

CMR data (δ_(c) (CDCl₃)) for the title compound: (1) tricyclic: (a) CH₂: 29.8/30.0, 30.0/30.2, (b) CH: 146.6/146.7/146.8, 140.8, 132.1/132.3,129.9/130.0, 125.9/126.3, 78.4/78.5, and (c) C: 119.6, 140.2/140.3,133.8, 134.3/134.4/134.6, 136.2/136.3, 154.6/154.8; (2) Piperazine: (a)CH₃ : 58.2, (b) CH₂ : 50.9/51.2/51.6, 54.3/54.4/54.7, 37.4/37.6,39.3/42.3, 67.6/67.7/69.6, and (c) CH: 50.0; and (3) piperazineN-substituent: (a) CH₂ : 36.6/36.8, (b) CH: 138.4/138.5, 126.4, 126.4,138.4/138.5, and (c) C: 133.8.

EXAMPLE 39 ##STR198##

The title compound from Example 11B above (1 equivalent) (2.7 g.) wasreacted with the title compound from Preparative Example 17D, of WO95/10516, (1.3 equivalents) (1.89 g.) and DEC (1.3 equivalents) (1.49g.), HOBT (1.3 equivalents) (1.05 g.) and N-methylmorpholine (1.3equivalents) (0.7876 g.) (0.8561 ml.) in dry DMF (80 ml.) at 25° C. for24 h. The product was isolated as described in Example 20A andchromatographed on a silica gel column using 0.5%(10% concentratedammonium hydroxide in methanol)-methylene chloride as the eluant to givethe title compound. Yield: 1.49 g., MH⁺ 677. ##STR199##

The title compound from Step A above (1.38 g.) was dissolved in methanol(10 ml.) and 10% (v/v) concentrated sulfuric acid in dioxane (30 ml.)was added and the reaction was run and worked up as described in Example20B. The product was chromatographed on a silica gel column using6-8%(10% concentrated ammonium hydroxide in methanol)-methylene chlorideas the eluant to give the title compound.

Yield: 0.7175 g., MH⁺ 577.

CMR data (δ_(c) (CDCl₃)) for the title compound: (1) tricyclic: (a) CH₂: 29.9/30.0, 30.1/30.2, (b) CH: 146.6/146.7, 140.7/140.8, 132.1/132.2,125.8/125.9, 129.9/130.0, 78.6, and (c) C: 119.5/119.6, 140.3/140.7,133.7, 134.7/134.8, 136.2/136.4, 155.0/155.1; (2) piperazine: (a) CH₃ :58.1, (b) CH₂ : 39.8/39.9/40.9, 51.3/51.5/51.9, 54.3/54.8/55.1, 36.2,67.9/68.0/69.7/69.8, and (c) CH: 49.7/49.8; and (3) piperazineN-substituent: (a) CH₂ : 45.9, 32.7, 32.7, 45.9, 39.0, (b) CH: 32.9; and(c) C: 169.7/170.2. ##STR200##

The title compound from Step B above (1 equivalent) (0.582 g.) wasdissolved in dry methylene chloride (6 ml.) and trimethylsilylisocyanate(6 equivalents) (0.6985 g.) (0.821 ml.) was added. The mixture wasstirred at 25° C. for 48 h. under argon. The mixture was diluted withmethylene chloride and washed with saturated aqueous sodium bicarbonate,water and then dried over magnesium sulfate. Filtration followed byevaporation gave the title compound that was purified on a silica gelcolumn using 3%(10% concentrated ammonium hydroxide inmethanol)-methylene chloride as the eluant to give the title compound.Yield: 0.4926 g., MH⁺ 620.

CMR data (δ_(c) (CDCl₃)) for the title compound: (1) tricyclic: (a) CH₂: 29.9/30.0, 30.1, (b) CH: 146.6/146.7, 140.7/140.8, 132.1/132.2,125.8/125.9, 130.0, 78.6, and (c) C: 119.5/119.6, 140.3, 133.8, 134.8,136.2/136.4, 154.9/155.0; (2) piperazine: (a) CH₃ : 58.1/58.2, (b) CH₂ :38.2/38.3, 51.2/51.5/51.8, 54.3/54.7/55.1, 36.2, 67.8/67.9/69.6/69.8,and (c) CH: 49.7; and (3) piperazine N-substituent: (a) CH₂ : 43.9/44.0,40.8/40.9, 40.8/40.9, 43.9/44.0, 39.1, (b) CH: 32.5; and (c) C: 157.5,169.3/169.9.

EXAMPLE 40 ##STR201##

To a suspension of Tentagel S® NH₂ Resin (Rapp Polymere Gmbh, Germany)(1.0 g, 0.28 mmol/g loading, 0.28 mmol) in DCM (1.0 mL) in a Merrifieldreaction vessel was added 4-(bromomethyl)-3-nitrobenzoic acid (1.12mmol, 0.29 g), HOBT (1.12 mmol, 0.15 g) and DIC (1.68 mmol, 0.21 g, 0.26mL). The resin shook at room temperature for 16 h and was then washedwith DCM (4×10 mL) and THF (3×10 mL). ##STR202##

The resin (0.28 mmol theoretical loading) was suspended in THF (10 mL)and treated with (aminomethyl)cyclopropane (5.6 mmol, 0.40 g, 0.49 mL)at room temperature for 16 h. The resin was then washed with THF (2×10mL). ##STR203##

The resin (0.28 mmol theoretical loading) is suspended in DCM (10 mL)and reacted with 1-N-FMOC-4-BOC piperazine-2-acetic acid (1.12 mmol,0.52 g), HATU (1.12 mmol, 0.43 g) and N,N-diisopropyethylamine (2.24mmol, 0.29 g, 0.39 mL). The resin shook at room temperature for 16 h andwas then washed with DCM (4×10 mL). The resin was then retreated withthe same mixture of reagents in a second coupling cycle of 16 h. Theresin was then washed with DCM (6×10 mL). ##STR204##

The resin (0.28 mmol theoretical loading) was washed once with DMF (10mL) and was then treated with a 30% solution of piperidine in DMF (totalvolume=10 mL) at room temperature for 30 min. The resin was then washedwith DMF (10 mL), methanol (2×10 mL) and DCM (3×10 mL). ##STR205##

The resin (0.28 mmol theoretical loading) was suspended in DCM (10 mL)and treated with (S)-(+)-α-methoxyphenylacetic acid (1.12 mmol, 0.19 g),HATU (1.12 mmol, 0.43 g) and N,N-diisopropylethylamine (2.24 mmol, 0.29g, 0.39 mL). The resin shook at room temperature for 16 h and was thenwashed with DCM (4×10 mL). ##STR206##

The resin (0.28 mmol theoretical loading) was treated with a 30%solution of TFA in DCM (10 mL) at room temperature for 1 h. The resinwas then washed with DCM (2×10 mL) and methanol (3×10 mL) and thentreated with a 20% solution of triethylamine in methanol (10 mL) for 30min. The resin was then washed with methanol (2×10 mL) and DCM (4×10mL). ##STR207##

The resin (0.28 mmol theoretical loading) was suspended in DMA (10 mL)in a round-bottomed flask and treated with ##STR208## (1.12 mmol, 0.38g), from Preparative Example 40 of WO 95/10516, and1,2,2,6,6-pentamethylpiperidine (1.12 mmol, 0.17 g, 0.20 mL). The resinwas stirred gently at 45° C. for 16 h and was then filtered and washedwith DCM (5×10 mL), DMF (3×10 mL) and methanol (3×10 mL). ##STR209##

The resin (0.28 mmol theoretical loading) was washed from the filterfunnel into a 25 mL round-bottomed flask with methanol (10 mL) andphotolysed (UVP Blak-Ray lamp, 360 nm) for 3 h. The resin was filteredand washed with methanol (3×10 mL) and DCM (3×10 mL). The solvent andwashings are combined and evaporated to dryness in vacuo giving compoundH.

By employing the processes described above, as well as the processesdescribed in WO 94/08051, as exemplified in Example 40, compounds of theformula: ##STR210## were prepared wherein R¹ and R² are defined in Table3 below.

                                      TABLE 3                                     __________________________________________________________________________    Example                                                                            R.sup.1           R.sup.2                                                __________________________________________________________________________    41                                                                                  ##STR211##                                                                                      ##STR212##                                            42                                                                                  ##STR213##                                                                                      ##STR214##                                            43                                                                                  ##STR215##                                                                                      ##STR216##                                            44                                                                                  ##STR217##                                                                                      ##STR218##                                            45                                                                                  ##STR219##                                                                                      ##STR220##                                            46                                                                                  ##STR221##                                                                                      ##STR222##                                            47                                                                                  ##STR223##                                                                                      ##STR224##                                            48                                                                                  ##STR225##                                                                                      ##STR226##                                            50                                                                                  ##STR227##                                                                                      ##STR228##                                            51                                                                                  ##STR229##                                                                                      ##STR230##                                            54                                                                                  ##STR231##                                                                                      ##STR232##                                            55                                                                                  ##STR233##                                                                                      ##STR234##                                            56                                                                                  ##STR235##                                                                                      ##STR236##                                            __________________________________________________________________________

EXAMPLE 56A ##STR237##

React the product of Preparative Example 2 following the procedure ofExample 1 Step A to obtain Compound (56A(i)). Compound 56A(i) (320 mg),CH₂ Cl₂ (2 mL), TFA (2 mL) and (C₂ H₅)₃ SiH (249 μL) were charged to aflask. The reaction mixture was stirred at room temperature for aboutthree hours. All the solvents were removed on a rotavap. HCl (1N) wasadded to dissolve the product and the resulting solution was washed withhexanes. The solution was stripped down on a rotovap and then HCl (1N)was added and the resulting solution was lyophilized to yield the titlecompound (56A(ii)). Mass Spec.: M+1=480.

The compounds in Tables 4-7 below exhibited biological activity atconcentrations below about 10 μM using an in vitro assay measuring theinhibition of FPT. Under the test protocols employed, there were certaincompounds within the scope of the invention which did not exhibitactivity. It is believed that such compounds would exhibit activityunder a different test protocol. For example, certain compounds whereinR¹ was: ##STR238## did not exhibit activity at the concentrationstested.

EXAMPLES 57-210

Compounds of the formula: ##STR239## were prepared, by proceduressimilar to those in Example 40, wherein R¹ and R² are defined in Table 4below. In Table 4 the numbers in the column for R¹ refer to the formulanumbers of the R¹ groups exemplified above. In Table 4, R² is --C(O)R⁶⁵(i.e., formula (84.0)). The numbers in the R² column refer to theformula numbers of the R⁶⁵ groups exemplified above. In Table 4, thecolumn labeled "EX" refers to the example number.

                  TABLE 4                                                         ______________________________________                                              R.sup.2             R.sup.2          R.sup.2                            EX    (R.sup.65)                                                                           R.sup.1 EX   (R.sup.65)                                                                          R.sup.1                                                                            EX    (R.sup.65)                                                                         R.sup.1                       ______________________________________                                        57    201.0  (S)-    58   201.0 143.0                                                                              59    201.0                                                                              147.0                                      110.0                                                            60    202.0  101.0   61   202.0 103.0                                                                              62    202.0                                                                              104.0                         63    202.0  105.0   64   202.0 136.0                                                                              65    202.0                                                                              137.0                         66    202.0  152.0   67   202.0 153.0                                                                              68    202.0                                                                              157.0                         69    202.0  160.0   70   202.0 161.0                                                                              71    202.0                                                                              136.0                         72    203.0  101.0   73   203.0 102.0                                                                              74    203.0                                                                              103.0                         75    203.0  104.0   76   203.0 105.0                                                                              77    203.0                                                                              106.0                         78    203.0  (S)-    79   203.0 113.0                                                                              80    203.0                                                                              118.0                                      110.0                                                            81    203.0  120.0   82   203.0 124.0                                                                              83    203.0                                                                              125.0                         84    203.0  137.0   85   203.0 143.0                                                                              86    203.0                                                                              152.0                         87    203.0  153.0   88   203.0 154.0                                                                              89    203.0                                                                              156.0                         90    203.0  157.0   91   203.0 160.0                                                                              92    203.0                                                                              161.0                         --    --     --      94   204.0 101.0                                                                              95    204.0                                                                              102.0                         96    204.0  103.0   97   204.0 104.0                                                                              98    204.0                                                                              105.0                         99    204.0  106.0   100  204.0 (R)- 101   204.0                                                                              123.0                                                         110.0                                         102   204.0  124.0   103  204.0 129.0                                                                              104   204.0                                                                              136.0                         105   204.0  137.0   106  204.0 152.0                                                                              107   204.0                                                                              154.0                         108   204.0  157.0   --   --    --   --    --   --                            111   205.0  101.0   112  205.0 120.0                                                                              113   205.0                                                                              124.0                         114   205.0  157.0   115  206.0 101.0                                                                              116   206.0                                                                              102.0                         117   206.0  104.0   118  206.0 105.0                                                                              119   206.0                                                                              122.0                         120   208.0  125.0   121  206.0 137.0                                                                              122   206.0                                                                              139.0                         123   206.0  152.0   124  206.0 157.0                                                                              --    --   --                            126   207.0  101.0   127  207.0 122.0                                                                              128   207.0                                                                              137.0                         129   208.0  101.0   130  208.0 103.0                                                                              131   208.0                                                                              104.0                         132   208.0  106.0   133  208.0 112.0                                                                              134   208.0                                                                              124.0                         135   208.0  137.0   136  208.0 152.0                                                                              137   208.0                                                                              153.0                         138   208.0  155.0   139  205.0 157.0                                                                              140   209.0                                                                              104.0                         141   209.0  137.0   142  209.0 157.0                                                                              143   210.0                                                                              101.0                         144   210.0  102.0   145  210.0 104.0                                                                              146   210.0                                                                              105.0                         147   210.0  120.0   148  210.0 124.0                                                                              149   210.0                                                                              125.0                         150   210.0  136.0   151  210.0 137.0                                                                              152   210.0                                                                              149.0                         153   210.0  150.0   154  210.0 153.0                                                                              155   210.0                                                                              155.0                         156   210.0  157.0   157  212.0 137.0                                                                              158   214.0                                                                              137.0                         159   214.0  148.0   160  215.0 125.0                                                                              161   216.0                                                                              124.0                         162   216.0  157.0   163  (S)-  101.0                                                                              164   (S)- 103.0                                                   217.0            217.0                              165   (S)-   107.0   166  (S)-  137.0                                                                              167   (S)- 138.0                               217.0               217.0            217.0                              168   (S)-   152.0   169  (S)-  157.0                                                                              170   (S)- 160.0                               217.0               217.0            217.0                              --    --     --      172  (R)-  122.0                                                                              173   (R)- 136.0                                                   217.0            217.0                              174   (R)-   137.0   175  (R)-  157.0                                                                              176   (R)- 161.0                               217.0               217.0            217.0                              177   219.0  147.0   178  220.0 157.0                                                                              179   221.0                                                                              117.0                         180   223.0  124.0   181  225.0 101.0                                                                              182   225.0                                                                              102.0                         183   225.0  103.0   184  225.0 105.0                                                                              185   225.0                                                                              106.0                         186   225.0  107.0   187  225.0 108.0                                                                              188   225.0                                                                              109.0                         189   225.0  (R)-    190  225.0 (S)- 191   225.0                                                                              112.0                                      110.0              110.0                                         192   225.0  113.0   193  225.0 119.0                                                                              194   225.0                                                                              120.0                         195   225.0  136.0   196  225.0 137.0                                                                              197   225.0                                                                              151.0                         198   225.0  152.0   --   --    --   200   226.0                                                                              106.0                         202   227.0  108.0   202  227.0 (R)- 203   227.0                                                                              148.0                                                         110.0                                         --    --     --      205  229.0 157.0                                                                              206   230.0                                                                              131.0                         207   230.0  137.0   208  230.0 161.0                                                                              209   231.0                                                                              137.0                         210   231.0  145.0   211  231.0 157.0                                                                              --    --   --                            ______________________________________                                    

EXAMPLES 211-248

Compounds of the formula: ##STR240## were prepared, by proceduressimilar to those in Example 40, wherein R¹ and R² are defined in Table 5below. In Table 5 the numbers in the column for R¹ refer to the formulanumbers of the R¹ groups exemplified above. In Table 5 R² is --CH₂C(O)R⁶⁵ (i.e., formula (86.0)). The numbers in the R² column refer tothe formula numbers of the R⁶⁵ groups exemplified above. In Table 5 thecolumn labeled "EX" refers to the example number.

                  TABLE 5                                                         ______________________________________                                              R.sup.2             R.sup.2         R.sup.2                             EX    (R.sup.65)                                                                           R.sup.1 EX   (R.sup.65)                                                                          R.sup.1                                                                            EX   (R.sup.65)                                                                          R.sup.1                       ______________________________________                                        211   202.0  105.0   212  202.0 120.0                                                                              213  202.0 140.0                         214   202.0  157.0   215  203.0 102.0                                                                              216  203.0 104.0                         217   203.0  120.0   218.0                                                                              203.0 124.0                                                                              219  203.0 137.0                         220   203.0  138.0   221  203.0 140.0                                                                              222  203.0 153.0                         223   203.0  156.0   224  205.0 138.0                                                                              225  205.0 152.0                         226   205.0  157.0   227  205.0 161.0                                                                              228  207.0 158.0                         229   208.0  120.0   230  208.0 146.0                                                                              231  208.0 157.0                         232   209.0  150.0   233  209.0 161.0                                                                              --   --    --                            235   211.0  120.0   236  213.0 147.0                                                                              237  214.0 139.0                         238   216.0  101.0   239  216.0 132.0                                                                              240  (S)-  148.0                                                                   217.0                               241   (R)-   102.0   242  (R)-  103.0                                                                              243  219.0 128.0                               217.0               217.0                                               244   221.0  125.0   --   --    --   246  226.0 103.0                         247   226.0  127.0   248  229.0 155.0                                                                              --   --    --                            ______________________________________                                    

EXAMPLES 249-280

Compounds of the formula: ##STR241## were prepared, by proceduressimilar to those in Example 40, wherein R¹ and R² are defined in Table 6below. In Table 6 the numbers in the column for R¹ refer to the formulanumbers of the R¹ groups exemplified above. In Table 6 R² is --C(O)R⁶⁵(i.e., (84.0)). The numbers in the R² column refer to the formulanumbers of the R⁶⁵ groups exemplified above. In Table 6 the columnlabeled "EX" refers to the example number.

                  TABLE 6                                                         ______________________________________                                              R.sup.2             R.sup.2         R.sup.2                             EX    (R.sup.65)                                                                           R.sup.1 EX   (R.sup.65)                                                                          R.sup.1                                                                            EX   (R.sup.65)                                                                          R.sup.1                       ______________________________________                                        249   202.0  157.0   250  203.0 129.0                                                                              251  203.0 157.0                         252   204.0  109.0   253  204.0 157.0                                                                              254  205.0 124.0                         255   210.0  154.0   256  215.0 112.0                                                                              257  (S)-  106.0                                                                   217.0                               258   (R)-   120.0   259  (R)-  143.0                                                                              260  219.0 106.0                               217.0               217.0                                               261   219.0  115.0   262  221.0 146.0                                                                              263  222.0 108.0                         264   222.0  132.0   265  222.0 151.0                                                                              266  225.0 101.0                         267   225.0  102.0   268  225.0 103.0                                                                              269  225.0 104.0                         270   225.0  106.0   271  225.0 108.0                                                                              272  225.0 (R)-                                                                          110.0                         273   225.0  112.0   274  225.0 124.0                                                                              275  225.0 136.0                         276   225.0  141.0   277  225.0 143.0                                                                              278  225.0 152.0                         279   225.0  157.0   280.0                                                                              228.0 101.0                                                                              --   --    --                            ______________________________________                                    

EXAMPLES 281-288

Compounds of the formula: ##STR242## were prepared, by proceduressimilar to those in Example 40, wherein R¹ and R² are defined in Table 7below. In Table 7 the numbers in the column for R¹ refer to the formulanumbers of the R¹ groups exemplified above. In Table 7 R² is --CH₂C(O)R⁶⁵ (i.e., formula (86.0)). The numbers in the R² column refer tothe formula numbers of the R⁶⁵ groups exemplified above. In Table 7 thecolumn labeled "EX" refers to the example number.

                  TABLE 7                                                         ______________________________________                                              R.sup.2             R.sup.2         R.sup.2                             EX    (R.sup.65)                                                                           R.sup.1 EX   (R.sup.65)                                                                          R.sup.1                                                                            EX   (R.sup.65)                                                                          R.sup.1                       ______________________________________                                        281   202.0  102.0   282  202.0 151.0                                                                              283  202.0 157.0                         284   203.0  157.0   285  212.0 150.0                                                                              286  (S)-  105.0                                                                   217.0                               287   221.0  159.0   288  223.0 149.0                                                                              --   --    --                            ______________________________________                                    

EXAMPLES 289-306

Compounds of the formula: ##STR243## could be prepared, if proceduressimilar to those in Example 40, were to be followed, wherein R¹ and R²are defined in Table 8 below. In Table 8 the numbers in the column forR¹ refer to the formula numbers of the R¹ groups exemplified above. InTable 8 R² is --C(O)R⁶⁵ (i.e., (84.0)) or --CH₂ C(O)R⁶⁵ (i.e., (86.0)).The numbers in the R² column refer to the formula numbers of the R⁶⁵groups exemplified above. In Table 8 the column labeled "EX" refers tothe example number.

                  TABLE 8                                                         ______________________________________                                               R.sup.2        R.sup.2                                                        (--C(O)R.sup.65)                                                                             (--CH.sub.2 C(O)R.sup.65)                               EX     (R.sup.65)     (R.sup.65)  R.sup.1                                     ______________________________________                                        289    203.0          --          124.0                                       290    204.0          --          121.0                                       291    204.0          --          122.0                                       292    204.0          --          125.0                                       293    206.0          --          136.0                                       294    217.0          --          125.0                                       295    217.0          --          157.0                                       296    225.0          --          142.0                                       297    228.0          --          125.0                                       298    228.0          --          109.0                                       299    --             209.0       136.0                                       300    --             209.0       137.0                                       301    --             225.0       140.0                                       302    --             225.0       141.0                                       ______________________________________                                    

ASSAYS

In some assays, FPT IC₅₀ (inhibition of farnesyl protein transferase, invitro enzyme assay) is determined by the methods described in WO95/10516. COS Cell IC₅₀ (Cell-Based Assay) and Cell Mat assay aredetermined by the methods described in WO 95/10516. GGPT IC₅₀(geranylgeranyl protein transferase, in vitro enzyme assay) and in vitrotumor activity can be determined by the methods disclosed in WO95/10516.

In some ways assays, the inhibition of farnesyl protein transferase wasassayed by measuring the transfer of ³ H!farnesyl from ³H!farnesylpyrophosphate to biotinylated Ras-peptide (biotin-KKSKTKCVIM)using the conditions described below for each 96-well plated to betested.

An assay buffer is prepared consisting of 40 mM Hepes, pH 7.5; 5 mMdithiothreitol; 20 mM magnesium chloride and 0.01 (v/v)% Igepalnon-ionic detergent.

A SPA (scintillation proximity assay) bead suspension is preparedconsisting of 50 mg of Streptavidin SPA beads (Amersham Life-Science)suspended in 2.5 mL of PBS (phosphate buffered saline). Immediatelyprior to running the assay a stop solution is prepared consisting of 480μL of the SPA bead suspension mixed with 6720 μL of a solutionconsisting of 250 mM EDTA (pH 8.0) and 0.5% Bovine Serium Albumin(Fraction V, 96-99% albumin).

In some assays, to determine FPT IC₅₀, an assay mixture is preparedconsisting of 480 μL of assay buffer and 3052.8 L of water. This mixtureis vortexed to homogeneity and 48 μL of the Ras peptide is added. Themixture is vortexed and 15.36 μL of FPP and 3.84 μL of ³ H!FPP are addedand the mixture vortexed again. 37.5 μL of this assay mixture and 2.5 μLof a DMSO solution (at test concentration) of the compound being testedare then added to each well of a Costar polypropylene U-bottommicrotiter plate. The plate is sonicated for 15 minutes at 37° C. andthen shaken for 15 minutes on a plate shaker. 10 μL of the enzyme(recombinant Human farnesyl protein transferase) is added to each wellusing a Beckman Biomek 2000. The plate is incubated at room temperaturefor 20 minutes and then quenched with 75 μL of the stop solution. 100 μLof the quenched reaction mixture from each well is then transferred to aWallac crosstalk-free microtiter plate using a Beckman Biomek 2000.Radioactivity is measured in a Wallac 1450 Microbeta plus liquidscintillation counter. Percent inhibition is calculated relative to anuninhibited control.

In some assays, to determine farnesyl transferase inhibition, an assaymixture is prepared consisting of 480 μL of assay buffer, 3052.8 μL ofwater and 240 μL of DMSO. This mixture is vortexed to homogeneity and 48μL of the Ras peptide is added. The mixture is vortexed and 15.36 μL ofFPP and 3.84 μL of ³ H!FPP are added and the mixture vortexed again. 40μL of this assay mixture is then added to each well of a Costarpolypropylene U-bottom microtiter plate, each well of which contains adry sample of the compound being tested. The plate is sonicated for 15minutes at 37° C. and then shaken for 15 minutes on a plate shaker. 10μL of the enzyme (recombinant Human farnesyl protein transferase) isadded to each well using a Beckman Biomek 2000. The plate is incubatedat room temperature for 20 minutes and then quenched with 75 μL of thestop solution. 100 μL of the quenched reaction mixture from each well isthen transferred to a Wallac crosstalk-free microtiter plate using aBeckman Biomek 2000. Radioactivity is measured in a Wallac 1450Microbeta plus liquid scintillation counter. Percent inhibition iscalculated relative to an uninhibited control.

Using the above procedures the following results were obtained:

    ______________________________________                                                       Activity in                                                                   COS Cells                                                                             Cell Growth Inhibition                                                Inhibition of                                                                         MAT Assay                                                                   RAS       Tumor  Normal                                  Compound FPT Inhibition                                                                            Processing                                                                              Cells  Cells                                   Tested   IC.sub.50 in μM                                                                        IC.sub.50 in μM                                                                      IC.sub.50 in μM                                                                   IC.sub.50 in μM                      ______________________________________                                        EX 1     19% @ 10 μM                                                                            --        --     --                                      EX 20, Step B                                                                          2           --        --     --                                      EX 21, Step B                                                                          2.1         --        --     --                                      EX 30    3.05        0         >50    >50                                     EX 31    6.39        0         12.5   18                                      EX 32-A  0.440       --        --     --                                               0.500                                                                EX 32-B  0.840       --        --     --                                               0.930                                                                EX 32-C  0.210       --        --     --                                               0.340                                                                EX 33    0.870       --        --     --                                               1.2                                                                  EX 34    2.5         --        --     --                                               2.3                                                                  EX 36    0.060       0.63      1.6    >25                                     EX 37, Step C                                                                          0.092       1.7       3.1    18                                      EX 38    0.034       <0.25     --     --                                      EX 39, Step B                                                                          0.069       --        --     --                                      EX 39, Step C                                                                          0.027       0.600     <1.6   >25                                     EX 41    0.077       --        --     --                                      EX 43    0.035       --        --     --                                               0.021                                                                EX 44    4.1         --        --     --                                               8.0                                                                  EX 46    0.900       --        --     --                                               1.4                                                                  EX 47    0.170       --        --     --                                      EX 48    >10         --        --     --                                               20                                                                   EX 50    9.0         --        --     --                                               13                                                                   EX 51    0.330       --        --     --                                               0.380                                                                EX 54    0.068       --        --     --                                      EX 55    0.600       --        --     --                                      EX 56    0.240       --        --     --                                               0.160                                                                EX 56A   18% @ 10.2 μM                                                                          --        --     --                                      ______________________________________                                    

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection.

Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.1 mg to 1000 mg, more preferably fromabout 1 mg. to 300 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

The amount and frequency of administration of the compounds of theinvention and the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regimen is oral administration of from 10 mg to 2000 mg/daypreferably 10 to 1000 mg/day, in two to four divided doses to blocktumor growth. The compounds are non-toxic when administered within thisdosage range.

The following are examples of pharmaceutical dosage forms which containa compound of the invention. The scope of the invention in itspharmaceutical composition aspect is not to be limited by the examplesprovided.

Pharmaceutical Dosage Form Examples EXAMPLE A

    ______________________________________                                        Tablets                                                                       No.     Ingredients      mg/tablet                                                                              mg/tablet                                   ______________________________________                                        1.      Active compound  100      500                                         2.      Lactose USP      122      113                                         3.      Corn Starch, Food Grade,                                                                       30       40                                                  as a 10% paste in                                                             Purified Water                                                        4.      Corn Starch, Food Grade                                                                        45       40                                          5.      Magnesium Stearate                                                                             3        7                                                   Total            300      700                                         ______________________________________                                    

Method of Manufacture

Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes.

Granulate the mixture with Item No. 3. Mill the damp granules through acoarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules.Screen the dried granules if necessary and mix with Item No. 4 and mixfor 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress themixture to appropriate size and weigh on a suitable tablet machine.

EXAMPLE B

    ______________________________________                                        Capsules                                                                      No.     Ingredient     mg/capsule  mg/capsule                                 ______________________________________                                        1.      Active compound                                                                              100         500                                        2.      Lactose USP    106         123                                        3.      Com Starch, Food Grade                                                                       40          70                                         4.      Magnesium Stearate NF                                                                        7           7                                                  Total          253         700                                        ______________________________________                                    

Method of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. AddItem No. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

What is claimed is:
 1. A compound of the formula ##STR244## wherein: Aand B are independently selected from H, halo or C₁ -C₆ alkyl;Z is N orCH; W is CH, CH₂, O or S, wherein the dotted line to W represents adouble bond which is present when W is CH; X is C, CH or N, wherein thedotted line connecting X to the tricyclic ring system represents adouble bond which is present when X is C; R¹ is selected from:1) a groupof the formula: ##STR245## or disulfide dimers thereof; 2) a group ofthe formula: ##STR246## 3) a group of the formula: ##STR247## wherein W,A and B are as defined above; 4) a group of the formula: ##STR248## 5) agroup of the formula: ##STR249## wherein R⁸⁰ is selected from H or--C(O)OR⁹⁰ wherein R⁹⁰ is a C₁ -C₆ alkyl group, and R⁸⁵ is a C₁ -C₆alkoxy group; and 6) a group of the formula: ##STR250## wherein: (a) Tis selected from: ##STR251## or a single bond; (b) x is 0, 1, 2, 3, 4, 5or 6;(c) each R^(a) and each R^(b) is independently selected from H,aryl, alkyl, alkoxy, aralkyl, amino, alkylamino, heterocyloalkyl,--COOR⁶⁰, --NH{C(O)}_(z) R⁶⁰ (wherein z is 0 or 1), or --(CH)_(w)S(O)_(m) R⁶⁰ (wherein w is 0, 1, 2 or 3, and m is 0, 1 or 2); or R^(a)and R^(b) taken together can represent cycloalkyl, ═N--O-alkyl, ═O orheterocycloalkyl with the proviso that for the same carbon, R^(a) is notselected from alkoxy, amino, alkylamino or --NH{C(O)}_(z) R⁶⁰ when R^(b)is selected from alkoxy, amino, alkylamino or --NH{C(O)}_(z) R⁶⁰ ; andwith the proviso that when T is a single bond, for the first carboncontaining R^(a) and R^(b), R^(a) and R^(b) are not selected fromalkoxy, alkylamino, amino or --NHR⁶⁰ ; and (d) R⁹² can represent H,alkyl, aryl, aryloxy, arylthio, aralkoxy, aralkyl, heteroaryl orheterocycloalkyl; R⁶⁰ represents H, alkyl, aryl or aralkyl; R⁴ is H orC₁ -C₆ alkyl; R² is selected from: --C(O)NR⁶ R⁷ or substituted (C₁-C₈)alkyl, wherein said substituted group has one or more substituentsselected from C(O)NR⁶ R⁷ ; R⁶ and R⁷ are independently selected from H,C₁ -C₄ alkyl, (C₃ -C₆) cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, substituted (C₁ -C₄)alkyl,substituted (C₃ -C₆)cycloalkyl, substituted aryl, substituted arylalkyl,substituted heteroaryl, substituted heteroarylalkyl or substitutedheterocycloalkyl, wherein said substituted groups have one or moresubstituents selected from: C₁ -C₄ alkoxy, aralkyl, heteroarylalkyl,--NO₂, C₃ -C₁₀ -alkoxyalkoxy, C₃ -C₆ cycloalkyl, aryl, --CN,nitrophenyl, methylenedioxy-phenyl, heteroaryl, heterocycloalkyl, halo,--OH, --C(O)R¹⁴, --C(O)NR⁶ R⁷, --N(R⁶)C(O)R¹⁴, --S(O)_(t) R¹⁴ or --NR⁹⁵R¹⁵ ; provided that R⁶ and R⁷ are not --CH₂ OH or --CH₂ NR⁹⁵ R¹⁵ whensaid R⁶, or R⁷ is directly bonded to a heteroatom; optionally, when R⁶and R⁷ are bound to the same nitrogen, R⁶ and R⁷ together with thenitrogen to which they are bound, form a 5 to 7 memberedheterocycloalkyl ring which optionally contains O, NR⁶, or S(O)_(t)wherein t is 0, 1 or 2; R⁹⁵ and R¹⁵ are independently H, C₁ -C₄ alkyl orarylalkyl; R¹⁴ is C₁ -C₄ alkyl, aryl or arylalkyl; n=0, 1, 2, 3 or 4;and t=0, 1 or 2;or pharmaceutically acceptable salts thereof.
 2. Thecompound of claim 1 wherein for R¹ :(a) T is selected from --C(O)--,--SO₂, or --C(O)--C(O)--; (b) x is 0, 1, or 2; (c) R^(a) and R^(b) areindependently selected from: (1) H; (2) NH{C(O)}_(z) R⁶⁰ wherein z is 0or 1, and R⁶⁰ is alkyl; (3) --(CH)_(w) S(O)_(m) R⁶⁰ wherein w is 0, 1, 2or 3, m is 0, 1 or 2, and R⁶⁰ is alkyl; (4) alkyl; or (5) C₁ -C₆ alkoxy;or (6) R^(a) and R^(b) taken together represent cycloalkyl; and (d) R⁹²is selected from (1) H; (2) aryl; (3) substituted aryl; (4) aralkyl; (5)aryloxy; (6) arylthio; (7) alkyl; (8) heteroaryl; (9) substitutedheteroaryl; (10) substituted heterocycloalkyl; or (11) substitutedalkyl; and wherein for said R² groups R⁶ and R⁷ are selected from: (1)H; (2) substituted alkyl; (3) alkyl; (4) cycloalkyl; (5) heteroarylalky;and (6) aralkyl wherein said aryl group is substituted.
 3. The compoundof claim 1 wherein R¹ is a group D, wherein D is --C(O)--CH₂ --R⁵,--C(O)--O--R⁵ or --C(O)--NH--R⁵, wherein R⁵ is pyridyl, pyridyl N-oxide,##STR252## a piperidinyl group of the formula ##STR253## wherein R¹¹represents H, C₁ -C₆ alkyl, haloalkyl or --C(O)--R⁹ wherein R⁹ is C₁ -C₆alkyl, C₁ -C₆ alkoxy or --NH(R¹⁰) wherein R¹⁰ is H or alkyl, or thegroup --C(O)--R⁹ represents an acyl radical of a naturally occurringamino acid.
 4. The compound of claim 1 wherein R¹ is a group selectedfrom a group of the formula: ##STR254##
 5. The compound of claim 1wherein R¹ is a group selected from: ##STR255##
 6. The compound of claim1 wherein R² is a group of formula ##STR256## wherein R⁶⁵ is selectedfrom a group of the formula: ##STR257## R² is selected from a group ofthe formula: ##STR258##
 7. The compound of claim 4 wherein R² is a groupof formula ##STR259## wherein R⁶⁵ is selected from a group of theformula: ##STR260##
 8. The compound of claim 1 wherein A is selectedfrom H or halo, B is halo, and Z is N.
 9. The compound of claim 8wherein A is H and B is Cl, or A is Br and B is Cl.
 10. The compound ofclaim 9 wherein W is --CH₂.
 11. The compound of claim 7 wherein A isselected from H or halo, B is halo, and Z is N.
 12. The compound ofclaim 11 wherein A is H and B is Cl, or A is Br and B is Cl.
 13. Thecompound of claim 12 wherein W is --CH₂.
 14. A compound selected from##STR261## a compound of the formula: ##STR262## wherein for eachcompound R¹ and R² are:

    __________________________________________________________________________    Example                                                                            R.sup.1           R.sup.2                                                __________________________________________________________________________    41                                                                                  ##STR263##                                                                                      ##STR264##                                            43                                                                                  ##STR265##                                                                                      ##STR266##                                            44                                                                                  ##STR267##                                                                                      ##STR268##                                            46                                                                                  ##STR269##                                                                                      ##STR270##                                            47                                                                                  ##STR271##                                                                                      ##STR272##                                            51                                                                                  ##STR273##                                                                                      ##STR274##                                            54                                                                                  ##STR275##                                                                                      ##STR276##                                            55                                                                                  ##STR277##                                                                                      ##STR278##                                            56                                                                                  ##STR279##                                                                                      ##STR280##                                            __________________________________________________________________________


15. A method for inhibiting the abnormal growth of cells comprisingadministering an effective amount of a compound of claim
 1. 16. Themethod of claim 15 wherein the cells inhibited are tumor cellsexpressing an activated ras oncogene.
 17. The method of claim 15 whereinthe cells inhibited are pancreatic tumor cells, lung cancer cells,myeloid leukemia tumor cells, thyroid follicular tumor cells,myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladdercarcinoma tumor cells or colon tumors cells.
 18. The method of claim 15wherein the inhibition of the abnormal growth of cells occurs by theinhibition of farnesyl protein transferase.
 19. The method of claim 15wherein the inhibition is of tumor cells wherein the Ras protein isactivated as a result of oncogenic mutation in genes other than the Rasgene.
 20. A pharmaceutical composition for inhibiting the abnormalgrowth of cells comprising an effective amount of compound of claim 1 incombination with a pharmaceutically acceptable carrier.
 21. A compoundof the formula ##STR281## wherein: A and B are independently selectedfrom H, halo or C₁ -C₆ alkyl;Z is N or CH; W is CH, CH₂, O or S, whereinthe dotted line to W represents a double bond which is present when W isCH; X is C, CH or N, wherein the dotted line connecting X to thetricyclic ring system represents a double bond which is present when Xis C; R¹ is selected from:1) a group of the formula: ##STR282## ordisulfide dimers thereof; 2) a group of the formula: ##STR283## 3) agroup of the formula: ##STR284## wherein W, A and B are as definedabove; 4) a group of the formula: ##STR285## 5) a group of the formula:##STR286## wherein R⁸⁰ is selected from H or --C(O)OR⁹⁰ wherein R⁹⁰ is aC₁ -C₆ alkyl group, and R⁸⁵ is a C₁ -C₆ alkoxy group; and 6) a group ofthe formula: ##STR287## wherein: (a) T is selected from: ##STR288## or asingle bond; (b) x is 0, 1, 2, 3, 4, 5 or 6;(c) each R^(a) and eachR^(b) is independently selected from H, aryl, alkyl, alkoxy, aralkyl,amino, alkylamino, heterocyloalkyl, --COOR⁶⁰, --NH{C(O)}_(z) R⁶⁰(wherein z is 0 or 1), or --(CH)_(w) S(O)_(m) R⁶⁰ (wherein w is 0, 1, 2or 3, and m is 0, 1 or 2); or R^(a) and R^(b) taken together canrepresent cycloalkyl, ═N--O-alkyl, ═O or heterocycloalkyl with theproviso that for the same carbon, R^(a) is not selected from alkoxy,amino, alkylamino or --NH{C(O)}_(z) R⁶⁰ when R^(b) is selected fromalkoxy, amino, alkylamino or --NH{C(O)}_(z) R⁶⁰ ; and with the provisothat when T is a single bond, for the first carbon containing R^(a) andR^(b), R^(a) and R^(b) are not selected from alkoxy, alkylamino, aminoor --NHR⁶⁰ ; and (d) R⁹² can represent H, alkyl, aryl, aryloxy,arylthio, aralkoxy, aralkyl, heteroaryl or heterocycloalkyl; R⁶⁰represents H, alkyl, aryl or aralkyl; R⁴ is H or C₁ -C₆ alkyl; R² isselected from: --C(O)OR⁶, --C(O)NR⁶ R⁷, C₂ -C₈ alkenyl, C₂ -C₈ alkynyl,substituted (C₁ -C₈)alkyl, substituted (C₂ -C₈)alkenyl, substituted (C₂-C₈)alkynyl, wherein said substituted groups have one or moresubstituents selected from:1) aryl, arylalkyl, heteroarylalkyl,heteroaryl, heterocycloalkyl, B-substituted aryl, B-substitutedarylalkyl, B-substituted heteroarylalkyl, B-substituted heteroaryl orB-substituted heterocycloalkyl, wherein B is selected from C₁ -C₄ alkyl,--(CH₂)_(n) OR⁶, --(CH₂)_(n) NR⁶ R⁷ and halo; 2) C₃ -C₆ cycloalkyl; 3)--N(R⁶)--C(O)R⁷ ; 4) --N(R⁶)--C(O)NR⁷ R¹² ; 5) --O--C(O)NR⁶ R⁷ ; 6)--SO₂ NR⁶ R⁷ ; 7) --N(R⁶)--SO₂ --R⁷ ; and 8) --C(O)NR⁶ R⁷ ; R⁶, R⁷ andR¹² are independently selected from H, C₁ -C₄ alkyl, (C₃ -C₆)cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, substituted (C₁ -C₄)alkyl, substituted (C₃-C₆)cycloalkyl, substituted aryl, substituted arylalkyl, substitutedheteroaryl, substituted heteroarylalkyl or substituted heterocycloalkyl,wherein said substituted groups have one or more substituents selectedfrom: C₁ -C₄ alkoxy, aralkyl, heteroarylalkyl, --NO₂, C₃ -C₁₀-alkoxyalkoxy, C₃ -C₆ cycloalkyl, aryl, --CN, nitrophenyl,methylenedioxy-phenyl, heteroaryl, heterocycloalkyl, halo, --OH,--C(O)R¹⁴, --C(O)NR⁶ R⁷, --N(R⁶)C(O)R¹⁴, --S(O)_(t) R¹⁴ or --NR⁹⁵ R¹⁵ ;provided that R⁶, R⁷ and R¹² are not --CH₂ OH or --CH₂ NR⁹⁵ R¹⁵ whensaid R⁶, R⁷ or R¹² is directly bonded to a heteroatom, and furtherprovided that R⁷ is not H for group 3); optionally, when R⁶ and R⁷ arebound to the same nitrogen, R⁶ and R⁷ together with the nitrogen towhich they are bound, form a 5 to 7 membered heterocycloalkyl ring whichoptionally contains O, NR⁶, or S(O)_(t) wherein t is 0, 1 or 2;optionally, when R⁷ and R¹² are bound to the same nitrogen, R⁷ and R¹²together with the nitrogen to which they are bound, form a 5 to 7membered heterocycloalkyl ring which optionally contains O, NR⁶, orS(O)_(t) wherein t is 0, 1 or 2; R⁹⁵ and R¹⁵ are independently H, C₁ -C₄alkyl or arylalkyl; R¹⁴ is C₁ -C₄ alkyl, aryl or arylalkyl; n=0, 1, 2, 3or 4; and t=0, 1 or 2;or pharmaceutically acceptable salts thereof. 22.The compound of claim 21 wherein for R¹ :(a) T is selected from--C(O)--, --SO₂, or --C(O)--C(O)--; (b) x is 0, 1, or 2; (c) R^(a) andR^(b) are independently selected from: (1) H; (2) NH{C(O)}_(z) R⁶⁰wherein z is 0 or 1, and R⁶⁰ is alkyl; (3) --(CH)_(w) S(O)_(m) R⁶⁰wherein w is 0, 1, 2 or 3, m is 0, 1 or 2, and R⁶⁰ is alkyl; (4) alkyl;or (5) C₁ -C₆ alkoxy; or (6) R^(a) and R^(b) taken together representcycloalkyl; and (d) R⁹² is selected from (1) H; (2) aryl; (3)substituted aryl; (4) aralkyl; (5) aryloxy; (6) arylthio; (7) alkyl; (8)heteroaryl; (9) substituted heteroaryl; (10) substitutedheterocycloalkyl; or (11) substituted alkyl; and wherein R² is selectedfrom: (1) --C(O)NR⁶ R⁷, and (2) substituted alkyl wherein thesubstituent is --C(O)NR⁶ R⁷ ; and wherein for said R² groups R⁶ and R⁷are selected from: (1) H; (2) substituted alkyl; (3) alkyl; (4)cycloalkyl; (5) heteroarylalky; and (6) aralkyl wherein said aryl groupis substituted.
 23. The compound of claim 21 wherein R¹ is a group D,wherein D is --C(O)--CH₂ --R⁵, --C(O)--O--R⁵ or --C(O)--NH--R⁵, whereinR⁵ is pyridyl, pyridyl N-oxide, ##STR289## a piperidinyl group of theformula ##STR290## wherein R¹¹ represents H, C₁ -C₆ alkyl, haloalkyl or--C(O)--R⁹ wherein R⁹ is C₁ -C₆ alkyl, C₁ -C₆ alkoxy or --NH(R¹⁰)wherein R¹⁰ is H or alkyl, or the group --C(O)--R⁹ represents an acylradical of a naturally occurring amino acid.
 24. The compound of claim21 wherein R¹ is a group selected from: ##STR291##
 25. The compound ofclaim 1 wherein R² is a group of formula ##STR292## wherein R⁶⁵ isselected from: ##STR293## R² is selected from a group of the formula: C₆H₅ CH₂ --, CH₃ CONH(CH₂)₄ --, --C(O)OC₂ H₅, ##STR294##
 26. The compoundof claims 21 wherein A is selected from H or halo, B is halo, and Z isN.
 27. The compound of claim 26 wherein A is H and B is Cl, or A is Brand B is Cl.
 28. The compound of claim 27 wherein W is --CH₂.
 29. Thecompound of claim 21 having the formula: ##STR295##
 30. A method forinhibiting the abnormal growth of cells comprising administering aneffective amount of a compound of claim
 21. 31. The method of claim 30wherein the cells inhibited are tumor cells expressing an activated rasoncogene.
 32. The method of claim 30 wherein the cells inhibited arepancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells,thyroid follicular tumor cells, myelodysplastic tumor cells, epidermalcarcinoma tumor cells, bladder carcinoma tumor cells or colon tumorscells.
 33. The method of claim 30 wherein the inhibition of the abnormalgrowth of cells occurs by the inhibition of farnesyl proteintransferase.
 34. The method of claim 30 wherein the inhibition is oftumor cells wherein the Ras protein is activated as a result ofoncogenic mutation in genes other than the Ras gene.
 35. Apharmaceutical composition for inhibiting the abnormal growth of cellscomprising an effective amount of compound of claim 21 in combinationwith a pharmaceutically acceptable carrier.